>> GOOD MORNING. I'M SO GLAD TO SEE YOU HERE. AT THE WORKSHOP ON CLINICAL TRANSLATIONAL MOLECULAR IMAGING AND TECHNOLOGY HERE AT LISTER HILL. MY NAME IS CHRISTINA LIU, PROGRAM DIRECTOR OF THE MOLECULAR IMAGING PROGRAM, NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING. AS A CO-ORGANIZER OF THIS MEETING, IT IS MY PLEASURE TO INTRODUCE OUR DIRECTOR, DR. RODERICK PEDIGREW WHO I GIVE YOU THE WELCOMING REMARK. >> THANK YOU, CHRISTINA. GOOD MORNING, EVERYONE. CAN YOU HEAR ME OKAY? IN THE BACK, SOUND CHECK. ALL RIGHT. THANK YOU. IT IS MY PLEASURE TO WELCOME EVERYONE TO THIS WORKSHOP, THE TITLE IS BEFORE YOU, WORKSHOP IS ON CLINICAL TRANSLATION OF MOLECULAR IMAGING PROBE AND TECHNOLOGY, THAT UNDERSCORES THE TASK AT HAND. THE OVERARCHING GOAL OF THIS WORKSHOP IS TO REALLY ADDRESS THE QUESTION OF HOW DO WE BEST ACCELERATE THE ADVANCES THAT HAVE BEEN OCCURRING IN THIS FIELD IN THE LABORATORY THE CLINIC. AND MAKE BEST USE OF THE SCIENCE AND DEVELOPMENTS THAT HAVE BEEN OCCURRING FOR THE LAST DECADE OR SO, IN ADDRESSING THE CHALLENGING PROBLEMS WE HAVE IN DIAGNOSING AND MONITORING DISEASE IN PATIENTS. IT IS INTERESTING THAT THIS PARTICULAR SLIDE THAT I SHOW YOU NOW ACTUALLY COMES FROM TALK THAT I GAVE EXACTLY TEN YEARS AGO THIS MONTH AS YOU CAN SEE FROM THE DATE ON THE SLIDE. FOR THOSE OF YOU WHO ARE NOT FAMILIAR WITH THE ISSR, THIS STAND FOR THE INTERNATIONAL SOCIETY FOR STRATEGIC STUDIES IN RADIOLOGY. IT'S LARGELY A GROUP OF RADIOLOGY CHAIRPERSONS AND INDUSTRY EXECUTIVES THAT MEET EVERY TWO YEARS TO TALK ABOUT FUTURE DIRECTIONS AND THE IMAGING SCIENCES. AND A DECADE AGO I WAS ASKED TO SPEAK ON THIS TOPIC. MOLECULAR IMAGING, WHERE DO WE GO FROM HERE? I FELT REASONABLY PREPARED TO DO THAT BECAUSE I HAD JUST ARRIVED AT THE NIH, I WAS STILL IN MY FIRST YEAR AS A DIRECTOR OF NIBIB. AT THAT TIME AS MANY OF YOU WILL REMEMBER, WE WERE UNDERGOING A STRATEGIC PLANNING PROCESS CALLED THE NIH ROADMAP. ONE OF THE AREAS PLANNEDDED IN THIS OVERARCHING MOLECULAR ROADMAP WAS MOLECULAR IMAGING. I CHAIRED THE GROUP THAT DISCUSSED THIS PARTICULAR AREA. THIS WAS THE RESULT OF DELIBERATIONS AND WAS THE VERY LAST SLIDE THAT I USED IN THE PRESENTATION THAT I GAVE TEN YEARS AGO. IT IS INTERESTING TO LOOK AT THIS BECAUSE IT MAPS OUT THE GOALS IDENTIFIED IN THIS WORKING GROUP AND THESE VARIOUS CATEGORIES OF TIME FRAMES ACHIEVE AND RISKS ASSOCIATED WITH ACHIEVING THEM. AND THE ONES THAT ARE BOLD ARE THE ONES THAT ACTUALLY IMPLEMENTED AS INITIATIVES AT THE NIH, EITHER AS INTRAMURAL INITIATIVES OR AS EXTRAMURAL INITIATIVES. THE ONE HIGHLIGHTED WITH THE RED ARROWS DID BECOME AN RAVISH SHOED IN 2004, FOCUSING ON IMPROVING THE SENSITIVITY OF MOLECULAR PROBES, SPECIFICALLY TARGETING SEVERAL ORDERS OF MAGNITUDE IN IMPROVEMENT WHICH BASED ON OUR ANALYSIS WE THOUGHT WAS NEEDED IN ORDER TO BE ABLE TO ACTUALLY DETECT SINGLE MOLECULAR EVENTS WHICH WAS THE TARGET. SO IDEAL LILY WE THOUGHT THAT AT THAT TIME A THOUSAND FOLD I BE REQUIRED AND CONSEQUENTLY THE RFA THAT WE ISSUED CHALLENGED THE IMMUNITY TO DEVELOP PROBES THAT HAD TEN TO 100 TIMES IMPROVEMENT IN DETECTABILITY THAT WAS EXPECTED TO BE DONE IN ANIMAL MODELS AND THE FOLLOW ON INITIATIVES FOUR YEARS LATER THEN WAS A CHALLENGE TO DO THIS IN VIVO AND IN HUMANS. IT'S ALSO INTERESTING TO NOTE IN THE UPPER RIGHT CORNER HERE WHICH WAS THE ULTIMATE GOAL THOUGHT OF IT THAT WE THOUGHT WOULD BE ACHIEVEED IN THIS TEN YEAR TIME FRAME. IT WAS OVER THE LONGEST PERIOD OF TIME AND CARRIED WITH IT THE HIGHEST RISK OF SUCCESS. BUT IF YOU READ THROUGH THIS, IT'S INTERESTING TO COMPARE WHERE WE ARE NOW A DECADE LATER, AS RELATIVE TO THIS GOAL DESCRIBED A DECADE AGO, SO AS IT READS THE GOAL WAS TO HAVE PERSONALIZED TREATMENT, THAT PHRASEOLOGY HAS NOW BEEN RECAST AS PRECISION MEDICINE. BUT I THINK WE'RE WORKING TOWARDS THAT SO PERSONALIZED TREATMENT WITH WITH IMAGING AS A METHOD FOR PATIENT EVALUATION SELECTION, MONITORING OF TARGETED THERAPEUTICS INCLUDING PHYSIOLOGIC PROFILING OF PATIENTS, CELLS AND TISSUE FUNCTION, BIOMOLECULAR IMAGING, GENOMICS, PROTEOMICS AND OTHER METHODS. THAT I THINK IS VERY GOOD DESCRIPTION OF WHAT WE NOW CALL PRECISION MEDICINE. INDEED THERE HAS BEEN SOME PROGRESS TOWARDS ACHIEVING THE GOAL. TO SOME EXTENT THIS IS NOW BEGINNING TO BE DEMONSTRATED PRIMARILY WITH MOLECULAR IMAGING AS PART OF A DIAGNOSTIC PROCESS THAT EVALUATES FLUIDS AND BODY TISSUES EXVIVO. SO I WANT TO END WITH THE SLIDE I BEGAN WITH. MOLECULAR IMAGING, WHERE DO WE GO FROM HERE. THIS AGAIN IS A QUESTION THAT IS ON THE TABLE AND BEING POSED TO THIS GROUP WHEN WE ARE DELIGHTD TO ASSEMBLE A IMPRESSIVE GROUP OF EXPERTS FROM ACADEMIA, INDUSTRY AND ALSO FROM GOVERNMENT TO TACKLE THIS QUESTION. I WANT TO EMPHASIZE THAT WE REALLY ARE TRYING TO IDENTIFY THE MOST COMPELLING OPPORTUNITIES THAT ARE ASSOCIATED WITH THESE OPPORTUNITIES WITH EMPHASIS ON NEEDS AND EMPHAS ON WHERE WE O CAN HAVE THE GREATEST IMPACT IN ADDRESS THING THE HEALTHCARE CHALLENGES THAT WE FACE. SO THE OVERALL GOAL IS TO ACCELERATE THE TRANSLATION OF MOLECULAR IMAGING ADVANCES TO HUMANS FROM THE LABORATORY. I WANT TO ACKNOWLEDGE AND THANK CHRISTINA LIU AND TONY SASTRE WHO HAVE TAKEN ON THE TASK OF ORGANIZING THIS WORKSHOP. THOSE OF YOU WHO HAVE DONE WORKSHOPS YOURSELVES KNOW HOW MUCH WORK IT TAKES TO DO THESE KINDS OF THINGS THAT NEEDS EFFORT THAT IMMEDIATELY MEETS THE EYE SO WE WANT TO ACKNOWLEDGE THAT AND THANK THEM FOR BRINGING US TOGETHER TODAY AND GIVING US THIS OPPORTUNITY TO LEARN FROM EACH OTHER AND ULTIMATELY HAVE GREATER POSITIVE IMPACT ON ADDRESSING SOME OF THE NATION'S HEALTHCARE CHALLENGES. BRIEFLY, THE AGENDA MORNING IS OUTLINED BEFORE YOU, TWO SESSIONS IN THE MORNING, TWO IN THE AFTERNOON, THE FIRST SESSION WILL ADDRESS NEEDS IN THE CLINICAL RESEARCH IN THE PATIENT CARE ARENA, FOLLOWED BY DISCUSSION OF ADVANCES AND CHALLENGES AN MOLECULAR PROBE DESIGN AFTER LUNCH. THEN WE MOVE TO A DISCUSSION OF CHALLENGES THAT THE INDUSTRY AND THE PHARMACEUTICAL COMPANIES ARE FACING AND A CLUE QUITE APPROPRIATELY WITH THIS SESSION CLINICAL TRANSLATION. SO THANK YOU FOR JOINING US, HOPE YOU ENJOY THE CONFERENCE, WE LOOK FORWARD TO LEARNING FROM EACH OTHER. KRISHNA. -- CHRISTINA. [APPLAUSE]: >> DR. MEDIGREW DESCRIBED THE SESSIONS IN THIS WORKSHOP SO I WON'T ELABORATE MUCH ON IT. THE TIME PROVIDED UNDER THE LEVEL COLUMN, WE HAVE FOUR SPEAKERS FOR SESSION ONE. BETWEEN 8:50 AND 9:55, THE SECOND SESSION WILL HAVE FOUR SPEAKERS AFTER LUNCH,SESSION 3 WITH THREE SPEAKERS AND THE FOURTH SESSION WILL HAVE ADDITIONAL THREE SPEAKERS. IN ORDER TO SAVE TIME WE WILL NOT INTRODUCE THE SPEAKERS EXTENSIVELY BEFORE THEY TALKS. RATHER WE ENCOURAGE YOU TO LOOK INTO THE DOCUMENTS THAT YOU WERE -- YOU HAVE AT HAND OR YOU HAVE UP LOAD THANK YOU OUR WEB SO IT ABOUT THE SPEAKERS. SOMETHING LOOK LIKE THIS. DUE TO GOVERNMENT REGULATION WE APOLOGIZE WE CANNOT PROVIDE REFRESHMENTS FOR THE MEETING. SO THIS INFORMATION FOR FOOD. FOR LUNCH FROM 12:15 TO 1:05, 50 MINUTES, YOU CAN CHOOSE TO GO TO THE LISTER HILL CAFETERIA, WHICH IS LOCATED IN THE BASEMENT. SO IF YOU Q. OUT TO THE THIS END AND TAKE THE STAIRS DOWN YOU WILL TAKE THE SHARP LEFT TURN, IT WILL LEAD YOU TO THE CAFETERIA LEVEL. IF YOU CHOOSE TO TAKE A WALK IN SUCH NICE WEATHER YOU CAN GO ACROSS THE STREET TO NATCHER HERE WE ARE, LISTER HILL NATCHER BUILDING. THEY HAVE A BIGGER CAFETERIA FIRST FLOOR. FOR BREAKS, ONE IN THE MORNING ONE IN THE AFTERNOON, ONLY 20 MINUTES TO COME TO LISTER HILL CAFETERIA FOR COFFEE, COOKIES WHATEVER YOU WANT. I WAS INSTRUCTED TO TELL YOU TELL YOU THERE'S NO FOOD OR DRINKS ALLOWED MANY THE AUDITORIUM, WATER IS ONLY ALLOWED FOR THE SPEAKERS AT THE PODIUM LEVEL. WE WOULD LIKE TO THANK THE FOLLOWING PEOPLE FOR THEIR HARD WORK. (INDISCERNIBLE) IS OUR DEPUTY DIRECTOR -- DR. BELINDA SETO IS DEPUTY DIRECTOR AND DR. PETER KERSHER HELPED US TREMENDOUSLY DURING THE ORGANIZATION PHASE. BARBARA CATILINA AND SEAN SIMILARS AS WELL AS IT WEB AND COMMUNICATION TEAMS NAMES LISTED BELOW. WE -- THEY ARE GREATLY APPRECIATED. WITHOUT THEM, THE WORKSHOP WILL NOT BE POSSIBLE. LASTLY FOR PEOPLE WITHOUT THE FINAL MEETING MATERIALS YOU CAN GO TO THE WEBSITE HERE UNDER MEETING EVENTS YOU CAN SEE THE FINAL MEETING MATERIALS. RELATED TO THIS MEETING. FOR PEOPLE VIEWING THE VIDEOCAST OF THIS SITE, YOU ARE ENCOURAGED TO E MALL YOUR QUESTIONS FOR THIS EMAIL ADDRESS AND PLEASE PUT SUBJECT TITLE QUESTION AND YOU CAN SEND YOUR QUESTION TO US. WE WILL PRESENT YOUR QUESTIONS AS TIME PERMITS AND AS APPROPRIATE. THIS MEETING WILL BE ARCHIVE AND VIDEO AT NIH VIDEOCAST WEBSITE IN THE FUTURE. THANK YOU. LET'S GO ON TO THE FIRST SESSION. THANK YOU. >> GOOD MORNING. I'M STEVE KROSNIAK PROGRAM DIRECTOR AN MEDICAL OFFICER NIB,B AND WANT TO ECHO DR. LIU'S WELCOME FOR EVERYBODY ATTENDING TO WHAT LOOKS LIKE IS GOING TO BE A VERY EXCITING MEETING. IT'S MY PLEASURE TO INTRODUCE THE SPEAKERS FOR THE FIRST SESSION ON CURRENT CHALLENGES AND NEEDS FOR CLINICAL RESEARCH AND PATIENT CARE. WE HAVE A VERY IMPRESSIVE GROUP OF SPEAKERS AND P I KNOW -- CERTAINLY LOOK FORWARD TO PRESENTATIONS, EVERYBODY SHOULD ENJOY THEM, FIRST SPEAKER IS DR. LYNNE JOHNSON COLUMBIA UNIVERSITY IN NEW YORK, NEW YORK PRESBYTERIAN HOSPITAL. HE WILL SPEAK TO US ABOUT THE DEVELOPMENT IMAGING PROBES FOR CVD CHALLENGES AND POSSIBLE BENEFITS. WELCOME, DR. JOHNSON. >> THANK YOU. THIS WAS A BIG TOPIC. A DIFFICULT ASSIGNMENT. I HAD TO DO A LOT OF THINKING FIRST BEFORE I DECIDED TO SELECT SOME AREAS THESE ARE ONES I SELECTED. FIRST IS IMMANAGING PROBE TO IDENTIFY PATIENTS AT HIGHEST RISK FOR CARDIOVASCULAR EVENTS FROM AMONG HIGH CARDIAC RISK FACTOR GROUPS. THE SECOND IS MYOCARDIAL PROFUSION IMAGING AGENT WITH IMPROVED PHARMACOKINETICS TO IDENTIFY PATIENTS WITH ACUTE CORONARY SYNDROME FROM ALL THOSE MANY PATIENTS THAT COME TO THE ED WITH CHEST PAIN SYNDROMES. THE THIRD PROBES FOR TARGETING VASCULAR BIOLOGY AND PERIPHERAL ARTERY DISEASE, PERIPHERAL ARTERY DISEASE IS NEGLECTED AREA FOR TREATMENT AND SPECIAL IMAGING. NEW PROBES FOR TARGETING MYOCARDIAL FIBROSIS FORMATION AND HEART FAILURE. THE FIRST ONE UNMET NEED TO IDENTIFY HIGH RISK ASYMPTOMATIC PATIENT WITH VULNERABLE PLAQUE. THESE ARE PATIENTS THAT ARE AT RISK FOR SIGNIFICANT CARDIAC -- CARDIOVASCULAR EVENT. STROKE, MYOCARDIAL INFARCTION OR SUDDEN CARDIAC DEATH. IF WE LOOK AT THIS PYRAMID, THIS IS TAKEN FROM DR. BROWN'S EDITORIAL IN THE REFERENCE YOU SEE BELOW. AT THE LOWER PART OF THIS PYRAMID IS MAJORITY OF THE POPULATION. THEY'RE AT VERY LOW RISK FOR THESE EVENTS. I SHOULD PREFACE, THESE ARE ASYMPTOMATIC PATIENTS. THE LOWEST RISK AT THE BOTTOM, LESS THAN .5% EVENT PER YEAR. THERE'S PROBABLY NOTHING COST EFFECT I'VE IN THIS GROUP OF PATIENTS BUT SOME AREAS WOULD BE POSSIBLY GWAS TO IDENTIFY SNPS THAT COULD IDENTIFY WITHIN THIS GROUP A HIGHERRYK GROUP. THE INTERMEDIATE GROUP 2.5% EVENT PER YEAR, MANY CLINICIANS USING THE CRP OR ANKLE BRACHIAL INDEX TO IDENTIFY PATIENTS AT RISK. THERE'S QUESTION IN THE LITERATURE, DISCUSSIONS WHERE WE SHOULD MOVE TO CORONARY ARTERY KALES L YUM SCORES AND CAROTID ARTTRY ULTRA SOWN. WE'RE TALKING SCREENING A LARGE NUMBER OF PATIENTS SO WE CAN'T DO ADVANCED IMAGING, IT WOULDN'T BE COST EFFECTIVE TO APPLY THAT TO LARGE POPULATION SO YOU HAVE TO GO WITH SIMPLE TESTS INEXPENSIVE AND EASY TO PERFORM. SO THE AREA I WANT TO LOOK AT CONCENTRATE ON HERE FOR NEW PROBE DEVELOPMENT OFFER GETTING TO THE CLINIC WITH PROBES THAT ARE ALREADY DEVELOPED WOULD BE THE VERY HIGH RISK GROUP. UP TO AND GREATER THAN 15% OF EVENTS PER YEAR, IF YOU REALIZE, THERE'S A HIGHER PERCENTAGE OF SMALLER NUMBER OF PATIENTS BUT WE'RE TALKING ABOUT A SCREENING TEST SO IT HAS TO BE COST EFFECTIVE. VARIOUS PLATFORMS NUCLEAR CT MRI COULD POSSIBLY BE CONSIDERED. THIS JUST IS A CARTOON SHOWING PROBES DEVELOPED AND PRE-CLINICAL INVESTIGATIONS. I SHOULD SAY THERE ARE OVER 500 REFERENCES OVER 15 YEARS. YOU CAN LOOK AT EVERY SIGHT THAT MOLECULAR BIOLOGY RESEARCH IDENTIFIED IN THE UNSTABLE PLAQUE IS TARGETED WITH ALL KINDS OF PLATFORMS, SIGNALS, VEHICLES, ANIMAL MODELS AND SO WHAT IS HAPPENED IN THE CLINIC? IT'S LIKE WE HAD A LOT OF HORSES STARTING THERE AT THE GATE. BUT NOTHING GOT OUT OF THE GATE. NONE OF THESE PROBES MADE IT INTO THE CLINIC. FOR BIOLOGICAL TARGETING WE HAVE INFLAMMATION WITH FDG BUT THAT WAS BECAUSE IT WAS DEVELOPED FOR CANCER AND TARGETS HIGH METABOLIC RATE AND THEREFORE INFLAMMATION AND HAS BEEN APPLIED TO SOME CARDIOVASCULAR DISEASES. APOPTOSIS IS NOW GOING INTO CLINICAL IMAGING, MOSTLY TARGETING FOR MYOCARDIAL NECROSIS AND HASN'T BEEN APPLYD TO THE VASCULATURE. SO HERE WE HAD A LOT OF POSSIBILITIES. AND NOTHING HAS MOVED FORWARD. HERE IS WHAT WE AIM AT. HISTOMORPHOLOGICAL CHARACTERISTICS OF PLAQUE TYPES. ON THE LEFT YOU HAVE STABLE PLAQUE. YOU CAN SEE -- YOU CAN SEE THE LUMIN HERE AND YOU CAN SEE THE VESSEL WALL. IF U DID A CORONARY ANGIOGRAM THIS WOULD BE 90% STENOSIS AND PROBABLY MAY WELL CAUSE SLOW LIMITATIONS IN ANGINA. HOWEVER, IT'S NOT VULNERABLE TO RUPTURE BECAUSE IT HAS A THICK OR FIBROUS CAP. THAT'S NOTS A CHARACTERISTIC THAT MAKES IT VULNERABLE. HERE IN THE MID SYSTEM A PLAQUE THAT RUPTUREED. HERE YOU CAN SEE IS THROMBUS, LUMIN AND WALL. ONE DIFFERENCE HERE, THE WALL, VESSEL, SEE HOW BIG IT IS COMPAREDDED TO THIS ONE? THAT'S POSITIVE REMODELING, HAS A LARGE NECROTIC CORE, INFLAMMATORY CELLS AND WHEN YOU LOCK IN AT HIGHER POWER YOU CAN SEE A RUPTURE THERE IN THE THIN CAP FIBROARTHEROMA WHICH CAUSED THE EVENT. SO THAT HAPPENS IN 75% OF PATIENTS WITH CORONARY OCCLUSION, WE GET TO CAROTID IT'S SIMILAR PATHOLOGY, HERE IS A DIFFERENT LESION, PLAQUE EROSION. LOOK AT THE LESION HERE. PERCENTAGE STENOSIS MAYBExÀ ABOUT 40%, YOU PROBABLY WOULDN'T KNOW YOU HAD A LEAGUE LIKE THIS. IN TERMS OF SYMPTOMS BUT WHAT CAN HAPPEN IN THE LESION ITSELF, THERE'S NO NECROTIC CORE. THESE WERE MOSTLY SMOOTH MUSCLE CELLS AND FIBROUS TISSUE. THESE LESIONS ARE SEEN ALMOST EXCLUSIVELY IN CIGARETTE SMOKERS. AND WOMEN WHO SMOKE CIGARETTES. WHAT HAPPENS HERE IS THERE'S EROSION AT THE SURFACE WHICH CAUSES THROMBUS FORMATION. WHEN THE PATIENT GETS TO -- IF THEY HAVE HAD SUCCESSFUL THROMBOLYTIC THERAPY YOU CAN'T FIND THE CULPRIT LESION BECAUSE IT'S SO DIFFERENT THAN THE OTHERS. SO RECENTLY DR. NURULA WENT THROUGH MANY -- THESE ARE FROM -- THE PATHOLOGY IS FROM DR. F R,EMANI WHO STUDIEDED PATIENTS OVER MANY USERS AT THE ARMED FORCES INSTITUTE OF PATHOLOGY AT THE MEMBERS THAT DIED FROM SUDDEN CARDIAC DEATH, HAD ACCESS TO THEIR HEARTS AND DID THESE PATHOLOGICAL STUDIES. IT'S A GREAT REPOSITORY. SO DR. NURULA TOOK 295 HEARTS FROM THESE PATIENTS TO SEE WHAT WERE VARIABLES MOST LIKELY TO PREDICT AN EVENT. DOWN HERE IT WAS A VERY THIN FIBROUS CAP, LARGE MACROPHAGES AN LARGE NECROTIC CORE. SOMA CROW PHAGOS IS AN OBVIOUS TARGET. WHAT ABOUT THE CORE? TWO THINGS LEAD TO THAT. ONE CAUSED BY RAPID PLAQUE GROWTH FROM ONE OF TWO THINGS. HEEL PLAQUE RUPTURE OR HEMORRHAGE. HEEL PLAQUE RUPTURE, YOU CAN SEE THE IMAGE HERE, WITH THE SPECIAL STAINING, THIS PURPLE STAINING IS FOR COLLAGEN. SO WITH LITTLE ARROW THERE YOU CAN SEE THERE USED TO BE A THIN CAP THIGHER ARTHEROMA THERE THAT RUPTURED BUT THE PATIENT NEVER KNEW, IT WAS NEVER ASSOCIATED WITH AN EVENT. IT SEALED OVER. BUT SUDDENLY THE VESSEL WENT FROM THAT TO A A LUMIN THAT SIZE. WHEN THIS OCCURRED, THIS PLAQUE RUPTURE WHICH WAS ASYMPTOMATIC, THERE ARE THROMBUS AVAILABLE TO IMAGE. HERE SOOT POSSIBLE TARGET. BUT WE'RE TALKING HERE A SMALL TARGET IN HUMAN BEING SO THAT MAY NOT BE VERY FEASIBLE. THIS, HOWEVER, IS AN AREA THAT HASN'T BEEN EXPLORED SUFFICIENTLY. THAT'S INTERPLAQUE HEMORRHAGE. THESE LITTLE TINY LITTLE VESSELS THAT ARE NORMAL IN EVERY ARTERY, IN ATHEROSCLEROTIC PLAQUE THEY'RE METH RICK. NAYTITION, SMALL VESSELS MOVE INTO THE MEDIA. IF YOU LOOK UNDER HISTOLOGY HERE WITH STAINING, WITH ALL THESE TINY CAPILLARY, THEY'RE PRONE TO RUPTURE. WHEN THEY RUPTURE YOU GET INTERPLAQUE HEMORRHAGE. SO THESE ARE A GOOD TARGET AND THEY'RE ALL KINDS OF RECEPTORS AND PROTEINS THAT COULD BE TARGETED ALPHA B BETA 3. THERE'S VEGF RECEPTORS, THIS HASN'T BEEN PURSUED. SO WHERE ARE WE NOW WITH CLINICAL IMMANNING OF CORONARIES? CORONARY CTA HAS BEEN USED IN SOME INTERESTING STUDIES. WHERE YOU CAN SEE UP HERE, WITH THE RED BOX YOU CAN SEE A LARGE PLAQUE THAT IS RELATIVELY FREE, HAS A LOW FIELD UNIT, AND IS PROBABLY THE CORE OF THIS PARTICULAR PLAQUE. YOU CAN SEE THE WALL IS BULGED OUT THERE, THAT'S POSITIVE REMODELING. SO THIS COULD BE A SIGN OF UNSTABLE PLAQUE. NOT ALL PLAQUES HAVE THIS FINDING. , THERE ARE OTHER PROBLEMS WHEN THERE'S CALCIUM IN THE LESION IT'S DIFFICULT TO SEE. HERE WE HAVE FDG. NOT DOING WELL WITH THIS. ANY RATE, THE FDG RIGHT UPPER CORNER YOU CAN SEE THE CIRCLES AROUND UPTAKE. SEVERAL STUDIES HAVE BEEN DONE IN PATIENTS WITH STINTS SO THEY HAVE GOT STINTS, THESE ARE RECENT MYOCARDIAL INFARCTION AREAS CULPRIT LESION, PRETTY EASY TARGET TO FIND BUT NEVERTHELESS SOME PATIENTS THEY STUDIED HAD CULPRIT LESIONS THAT DIDN'T HAVE FDG UPTAKE. IN ADDITION, THERE IS THE PROBLEMr MYOCARDIUM HERE. THE UPTAKE IN THE MYOCARDIUM, IT'S A SUBSTRATE METABOLISM. SO FDG FOR -- AND THAT'S -- WE'RE NOT GETTING TO GATING AND ALL THE OTHER PROBLEMS INVOLVED. IT'S JUST I DONE THINK GOING TO GO IRIN. THIS IS KIND OF INTERESTING DOWN HERE. THE OCT, ULTRASOUND, ARE NOW NOT INFREQUENTLY BEING PERFORMED BY INTERVENTIONAL ANGIOGRAPHIES WHEN THEY PUT IN STINTS. HERE IS A PATIENT WITH A RECENT MYOCARDIAL INFARCTION, WHEN THEY GOT IN THE CATH LAB THEY DID ANGIOGRAM AND DIDN'T SEE ANY CULPRIT LESIONS SO THEY PUT IN THE OCT AND LOW AND BEHOLD THEY SAW A LESION LIKE THIS. THIS IS FROM THE PATHOLOGY WE LOOKED AT YOU RECOGNIZE PLAQUE EROSION. SO THIS WAS NOT A THIN CAP FIBROMYOMA, IT HAD ERODED, AND THIS WAS A CIGARETTE SMOKER SO THIS TECHNOLOGY HAS PROMISE. THIS IS NOT SOMETHING THAT'S USED FOR SCREENING OBVIOUSLY BUT IT'S SOMETHING WHEN A PATIENT COMES WITH A EVENT YOU CAN FIND OTHER VESSELS AT RISK. USING THIS KIND OF TECHNOLOGY. SO WE'RE GOING TO MOVE TO CAROTIDS, STROKE IS LEADING CAUSE OF DEATH, IT'S EASIER TARGET THAN CORONARY, LESS ATTENUATION, IT DOESN'T MOVE. ULTRASOUND IS CURRENTLY USED. BUT THERE ARE PROBLEMS HERE. WITH TECHNICAL ASPECT AND PERSPECTIVE TRIALS HAVEN'T -- USING THIS AS A MARKER HAVEN'T BEEN PARTICULARLY SUCCESSFUL INCLUDING FIGURING OUT THE SIZE OF THE LESION WHEN YOU HAVE GOT LESIONS THAT INVOLVE BIFURCATION AS SHOWN IN THAT CARTOON. WHAT IS PATHOLOGY CAROTID PLAQUE? THEY'RE SIMILAR. YOU CAN SEE THE ARROW TO WHETHER THERE WAS RUPTURE OF THIN CAP FIBROARTHEROMA BUT SOMETHING DIFFERENT THAN CORONARY CIRCULATION IN THE CAROTID CIRCULATION IS PARTICULARLY PRONE TO INTERPLAQUE HEMORRHAGE. THE CORONARIES ARE ALSO BUT THE CAROTID MORE SO. IF YOU LOOK IN THE CHART ON THE RIGHT THERE, YOU LOOK DOWN AS PERCENTAGE OF VARIOUS PATHOLOGIES AND LESIONS THAT LED TO STROKE YOU CAN SEE THAT HEMORRHAGE IS 65% WHICH IS FAR UP THERE. OF COURSE INFLAMMATION IS ALSO. BUT TO BE ABLE TO TARGET HEMORRHAGE WOULD BE USEFUL. IN FACT, THAT'S WHAT DR. HATSUKAMI AND COLLEAGUES PUBLISHED A BUNCH OF PAPERS USING MR. MY UNDERSTANDING IS THIS IS 1.5 T UNITS THAT ARE AVAILABLE CLINICALLY. AND DOESN'T HAVE INTO APOLOGETIC COMBATALINIUM, SPECIAL CONTRAST MULTI-WEIGHTED PROTOCOLS, HE'S ABLE TO SEE THE TISSUE DEFINITION NICELY. AND YOU CAN SEE IN THE RIGHT UPPER PANEL CORRELATION WITH PATHOLOGY, IF YOU DO GIVE YOU CAN GET IT LOOKING AT FIBROUS CAP BUT ON THE BOTTOM HE SHOWS IDENTIFICATION OF INTERPLAQUE HEMORRHAGE IN PATIENT THAT THEN HAD A SERIAL STUDY 18 MONTHS LATER, YOU CAN SEE ON THE BOTTOM HOW THE PLAQUE HAS EXPANDED DRAMATICALLY. THAT'S THE EFFECT INTERPLAQUE HEMORRHAGE HAD ON EVOLUTION OF DISEASE. TARGETING PROBES? FDG T FIRST STUDY THAT KIM OUT, ROD'S PAPER SHOWN ON THE TOM TOP HERE, EVERYONE GOT QUITE ENTHUSIASTIC. YOU CAN SEE AREA OF PLAINMATION IN THE CAROTID ARTERY. BUT SOME SUBSEQUENT PAPERS I HAD ONE BELOW, IT WAS MERGED, FDG STUDY WAS MERGED WITH MR. ON THE MR WITH ARROW ON THE BOTTOM YOU CAN SEE THE PLAQUE PATHOLOGY IS FAIRLY WELL IDENTIFIED. BUT PUT THE FDG ON ANION WHAT I'M LOOKING AT, BLOOD POOL. SO I THINK THERE ARE PROBLEMS HERE, THERE'S BLOOD POOL ACTIVITY, ADJACENT TISSUE UPTAKE AND DIABETICS ARE DIFFICULT WHEN YOU INJECT ANY DIABETIC YOU GIVE FDG TO IN TERMS OF CONTROL BLOOD GLUCOSE. SO BACK TO TRIANGLE AND CHALLENGE OF IMAGING. SHOULD WE USE TWO TESTS, WE'RE TALKING SCREENING. RELATIVELY SMALL NUMBER OF PATIENTS BUT STILL A FAIRLY LARGE NUMBER OF PATIENTS, ALREADY HIGH RISK IDENTIFIED BY OTHER RISK FACTORS. TWO TESTS OR ONE TEST? TWO TESTS, MRI WITH MULTI-CONTRAST WEIGHTING SEEMS TO BE MAYBE THERE, WE DON'T KNOW. IT HAS TO BE INVESTIGATED IN POPULATION BASED STUDIES, FOR THE CORONARIES WE AREN'T ANYWHERE. DO WE NEED A SINGLE TEST OR -- IN OTHER WORDS COULD WE USE A SINGLE TEST, IS IT POSSIBLE TO IMAGE CIRCUMSTANCE LAGS IN THE SAME SESSION? THIS MAY DETERMINE THE IMMANAGING PLATFORM, IT NOT SUCCESSFUL WITH THE CORONARIES BUT NUCLEAR MAYBE THE WAY TO GO. YOU NEED HIGH TARGET THE BACKGROUND, SHORT TIME FROM INJECTION TO IMAGING. WHAT TARGET WOULD YOU GO AFTER? SOMETHING MORE SPECIFIC THAN FDG PLAQUE ANGIOGENESIS, INTRAVAS CAN YOU ALREADY THROMBUS IS ALSO A GOOD TARGET, SIGNAL NOISE AND PLAQUE EROSION. THIS IS DIFFERENT PATHOLOGY AND YOU MAY HAVE A SPECIAL TEST FOR SMOKERS. FOR A SINGLE PROBE THIS IS AN EXAMPLE OF SOMETHING WE HAVE DONE. THE QUESTION IS, WITH THE MOLECULAR IMAGING USING RADIONUCLIDE, IS THE BEE I DON'T KNOW LOCALIZED TO VULNERABLE PLAQUE SUFFICIENT TO MAKE THAT IDENTIFY THE LOCATION AND THE PATIENT. HERE WE HAVE A HYPERLIPIDEMIC PIG, THESE PIGS HAVE CHOLESTEROL LEVELS ABOUT IN THE 7 TO 800 LEVEL. THIS IS 12 MONTH OLD. WHAT WE DID IS WE INJECTED THEM WITH VIDEO LABELED ANTI-RAGE ANTIBODY, RAGE IS A MULTI-LIGAND RECEPTOR PRESENT IN MANY DISEASES INCLUDING ATHEROSCLEROSIS AND THE SIGNALING PATHWAYS, THE CASCADE FROM IT LARGELY IN ATHEROSCLEROSIS HAVE TO DO WITH INFLAMMATION, ALSO APOPTOSIS. WE THOUGHT IT A GOOD PROBE FOR ATHEROSCLEROSIS IMAGING AND DEVELOPED RADIO LABELED ANTIBODY. HERE IS THE PIG WITH TWO BEDS, THE NECK AND THE CHEST. WE COULD SEE FOCAL UPTAKE IN THE CROWD DID ARTERY. WITH THIN CAP ATHEROMA. THIS IS WITHOUT BELLS AND WHISTLES, THE REASON WE IDENTIFYD TO CORONARIES ON HISTOLOGY AND EXVIVO WAS THERE WAS VERY LITTLE UPTAKE IN THE HEART. LESS THAN .3% OF INJECTED DOSE PER GRAM. I'M GOING TO QUICKLY MOVE TO THE OTHER AREAS HERE. PATIENTS PRESENTING WITH CHEST PAIN TO THE EMERGENCY ROOM. THIS IS A LARGE PROBLEM. 5.5 MILLION PATIENTS COME TO THE EMERGENCY ROOM, BASED ON CLINICAL CRITERIA, LEVELS 1, 2 OR 3. LEVEL 3 MOST HOSPITALS GO 24 HOUR OBSERVATION AND SOME GET CORONARY CTAs, IN OUR HOSPITAL, IN HOSPITALS WE DO THE STRESS PROFUSION IMAGING. THE NEW CAMERAS WITH THE CCT CRYSTALS ALLOW VERY RAPID ACQUISITION TIMES. HOWEVER, THE RADIO TRACERS HAVEN'T CAUGHT UP WITH THE TECHNOLOGY FOR IMAGING ON THE CAMERAS. FOR INSTANCE, MAYBE IT HAS LOW EXTRACTION FRACTION HIGH SELECT UPTAKE WHICH REDUCES IMAGE QUALITY AND SENSITIVITY, LONG MYOCARDIAL RESONANCE TIME. TWO INJECTIONS TAKES THE PATIENT HALF THE DAY. MORE IDEAL AGENT WOULD HA3 HIGH MYOCARDIAL EXTRACTION SHORTER TIME LESS UPTAKE. HERE IS THE MATCH TO FIND THE TRACE TORE MATCH THE CAMERA. AND WE'RE DONE WITH THESE PATIENTS WITH A HALF HOUR, IN AND OUT OF THE NUCLEAR LAB WHICH MAKES BIG IMPACT CLINICALLY. PERIPHERAL ARTERY DISEASE IS COMMON CONDITION. ONE IN THREE DIABETICS OVER AGE 50 ARE AFFECTED. 20% PATIENTS OVER AGE 70. IT PRODUCES SYMPTOMATIC LEG PAIN WITH EXERTION AND DIABETICS, PARTICULARLY MALIGNANT DISEASE LEADING TO BREAST PAIN, GANGRENE REQUIRING AMPUTATION. NO CURRENT THROUGHITHER BYES ARE EFFECTIVE AND INTERVENTIONAL CATHETER APPROACHES HAVE TO BE PERFORMED. WHAT IS THE CURRENT IMAGING? WHERE ARE WE? IT HASN'T CHANGED IN 20 YEARS, IT'S AIMED LOOKING FOR FLOW AND FLOW LIMITING OKAY COLLUSIVE DISEASE LATER MANIFESTATIONS OF THE DISEASE. THERE'S THE ANKLE BRACHIAL INDEX WHICH IS NOT VERY SENSITIVE. OTHER RADIOTEEN TESTS ARE MOSTLY ULTRASOUND AND THEN ONCE YOU IDENTIFY REDUCED FLOW THEN YOU STILL HAVE TO DO ANGIOGRAM TO IDENTIFY THE SITES. I'M SHOWING PICTURES BECAUSE I HAVE SEEN THEM RECENTLY AND I LIKE IT BECAUSE THEY USE SIMPLE IMAGING TECHNOLOGY. ONE ON THE LEFT IS BY DR. PIPANOS AND HIS GROUP. HE'S LOOKING AT THE MUSCLES IN THE LEG. SO WHAT HAPPENS WHEN THERE'S CHRONIC ISCHEMIA, WHAT HAPPENS TO THESE MUSCLES? TURNS OUT THEY JUST GET REPLACEDDED BY FIBROSIS, SHRIVEL UP, YOU CAN SEE THAT CLINICALLY IN THESE PATIENTS THEY HAVE MARKED WASTING OF THEIR LOWER EXTREMITIES AND CAN'T WALK SO THE CT HERE FROM NORMAL TO NEAR END STAGE DISEASE YOU CAN SEE THAT BY DOING A ROUTINE CT. THIS GIVES AN ASSESSMENT OF WAY OF QUANTIFYING POTENTIALLY FOR EFFECTIVE TREATMENT. THIS IS NOT PROBE, NOT SUPER FANCY BUT I THINK IT'S SMART. THE PICTURE ON THE RIGHT IS AN INTERESTING ONE. THIS IS USING A VERY OLE RADIO TRACER, BEEN AROUND SINCE 1974. SODIUM FLUORIDE, A BONE IMAGING AGENT. THIS GROUP HAS BEEN LOOKING AT UPTAKE IN BLOOD VESSELS. HERE YOU CAN SEE THE UPTAKE IN THE ARTERIES IN THE LOWER LEGS. WHAT SIGNIFIES IS MEDIAL ELASTIC CALCIFY -- COMMON IN OLDER PEOPLE WITH HYPERTENSION. ONE MAJOR CAUSE FOR SYSTOLIC HYPERTENSION AND POST PRESSURES. THE SYSTOLIC -- PUTS MORE ON THE HEART AND KAWING LVH AND HEART PRESSURE. THIS IS -- USING THE OLD TRACER THAT'S BEEN AROUND FOREVER YOU CAN IDENTIFY THE PRESENCE AND BIOLOGY WHICH A GOOD TARGET FOR TREATMENT BECAUSE THAT CAUSES THE CALCIUM LEVEL TO DECREASE IN VESSELS. PERIPHERAL ARTERY DISEASE ISN'T JUST A DISEASE, THE LARGE VESSEL S, AM I OVER TIME? NOT JUST LARGE VESSELS BUT ALSO SMALL VESSELS. ON THE LEFT HERE AT THE TOP YOU CAN SEE VERY OLD PAPER, PRETTY OLD PAPER, AMERICAN JOURNAL PATHOLOGY 1995. THESE WERE SMALL BLOOD VESSELS FROM THE BASE, SOME OF THE LARGE ARTERIES OF PATIENTS WITH PERIPHERAL ARTERY DISEASE AND STAINED FOR RAGE, RAGE RECEPTOR. SO RAGE IS PRESENT IN A LOW LEVEL IN ALL THE ENDOTHELIUM AND BLOOD VESSELS NORMALLY. IN THE PRESENCE OF DIABETES AND PRESENCE OF HIGH LIPIDS AND OTHER DISORDERS, THESE RAGE LIGANDS GET UP REGULATED, BIND THEM, RAMMING EXPRESSION INCREASES. WHAT HAPPENS THAT CAUSES ENDOTHELIAL DYSFUNCTION AS WELL AS ATHEROSCLEROSIS. SO HERE WE HAVE THE PIG. ON THE BOTTOM RIGHT, HIND LEGS OF PIGS, THE TOP PANEL IS FARM PIG APPROXIMATE BOTTOM IS HYPERLIPIDEMIC PIG. YOU CAN SEE THE RADIO TRACER UPTAKE THE DIFFUSE IN LOWER LIMBS, NOT LOCATED TO THE VESSELS AND WHEN YOU LOOK AT THE -- YOU CAN SEE THE RAGE STAINING IN SMALL BLOOD VESSELS SO DIFFUSE VASCULAR DISEASE, RAGE IS A TARGET, THERE'S OTHER TARGETS WE CAN GO AFTER FOR THE LOWER EXTREMITIES. WHAT HAPPEN IT IS DIABETES WHICH IS INTERESTING AS RAGE IS EXPRESSED INCREASED EXPRESSION IN -- PARTICULARLY IN DIABETICS WITH HIGH GLUCOSE, WHAT HAPPENS IS THAT THE RAGE EXPRESSION IS EVEN MORE WILDLY#H; IN PRESENCE OF ISCHEMIA. THESE WERE PLAIN HYPERLIPIDEMIC PIGS. THESE MICE HERE WE ACTUALLY LIE GATED THE FEMORAL ARTERY AND SHOWED INCREASE EXPRESSION OF RAGE. AS RAGE INCREASES ANGIOGENESIS DECREASES, IT'S A GOOD TARGET FOR PERIPHERAL HIM DISEASE, AT THE LOWER RIGHT HAND CORNER YOU CAN SEE WITH THE MOUSE WITH WE WERE ABLE TO IMAGE ANGIOGENESIS WITH THE VEGF BUT YOU CAN ALSO DO IT WITH BETA 3. FINALLY, THIS IS JUST VERY QUICK. MYOCARDIAL DISEASE F. THERE'S ONE THING THAT I WANT TO FOCUS ON HERE, MYOCARDIAL FIBROSIS. IT IS PRESENT IN EVERY ETIOLOGY OF HEART DISEASE, ISCHEMIC HYPERTENSIVE, RESTRICTIVE MYOCARDITIS, EVERYTHING. REPLACEMENT OF HEAR TISSUE BY FIBROSIS, A LOT OF REASONS THAT LEAD TO THAT. WHAT'S INTERESTING IS WHAT CAUSES THIS IS THESE MYOFIBROBLASTS, THESE ARE CELLS THAT PRODUCE COLLAGEN AND CAUSE PROBLEMS THAT CAN BE REPAIRTIVE BUT ALSO LEAD TO HARM. THERE'S LOTS OF POTENTIAL TARGETING SIGHTS ON THESE FIBROBLASTS PURSUED BY INVESTIGATORS. YOU CAN GO TO THE LITERATURE, ALPHA SENSOR IMAGING OR ALPHA B BETA 3. THERE ARE LIMITATIONS TO BOTH FOR A VARIETY OF REASONS. THERE ARE OTHER TARGETS THAT ARE POSSIBLY CAN BE USED TO IDENTIFY, SO SUMMARY, IMAGING PROBE THAT IDENTIFY PATIENTS WITH VULNERABLE PLAQUE FROM THOSE HIGHEST CARDIOVASCULAR RISK IS HIGH IMPACT. IMPROVE LARGE NUMBERS OF CHEST PAIN WITH MYOCARDIAL PROFUSION IMAGING AGENT. PROBING THE BIOLOGY IS UNMET NEED. NEW PROBES TARGETING MYOFIBROBLASTS -- MOST TREATMENT FOR SEVERE HEART FAILURE FOCUS ON PREINVENTORYING OR REDUCING FIBROSIS, SOME OF THE DRUGS, THE LVAD, ALL OF THOSE. IT WOULD BE NICE TO HAVE AN AGENT WHERE THEY CAN FOLLOW. THIS THANK YOU. [APPLAUSE] >> IN THE INTEREST OF TIME WE WON'T TAKE QUESTIONS, THERE WILL BE AN OPPORTUNITY DURING THE PANEL SESSION AFTER THE FIRST TWO GROUPS OF SPEAKERS TO ASK QUESTIONS AND THERE WILL BE LOTS OF INTERESTING DISCUSSION. SO AT THIS POINT, IT'S MY PLEASURE TO WELCOME MAREN LAUGHLIN FROM NIDDK AT HIPPOTO TALK CLINICAL NEEDS FOR MOLECULAR IMAGING AND DIABETIC AND METABOLIC DISEASES. THANK YOU. >> IT'S NICE TO BE HERE. THANK YOU SO MUCH FORGIVING ME THE OPPORTUNITY TO. COME AND TELL YOU ABOUT THE SORT OF THING THAT NIDDK IS INTERESTED IN. I HAVE TO SAY THAT AFTER SUCH A BEAUTIFUL TALK, TALKING ABo‡M THE CLINICAL NEEDS FOR INDIVIDUAL PATIENTS, GOING TO STEP BACK INTO THE RESEARCH REALM. IT TURNS OUT DESPITE THE FACT THAT WE STUDIED WE KNOW VERY LIFT ABOUT THE NATURAL HISTORY OF MOST OF OUR DISEASES. THE REASON IS BECAUSE MANY TISSUES INVOLVED ARE DIFFICULT TO GET AT FROM A CLINICAL POINT OF VIEW WE CANNOT BIOPSY THE PANCREAS, FOR INSTANCE. WE KNOW LITTLE ABOUT THE PATHOGENESIS AND NATURAL HISTORY OF DIABETES, THAT'S WHY AT LEAST SOME NEEDS FROM MOLECULAR IMAGING ARE FOCUSED ON. SO THESE ARE GOALS WE'LL TALK ABOUT TODAY. PANCREATIC BETA CELL, TO UNDERSTAND THE PATHOGENESIS OF DIABETES IN GENERAL AND ALSO FOLLOW DISEASE IN INDIVIDUAL PATIENTS. ADIPOSE TISSUE AND PEOPLE. NEWLY DISCOVERED TISSUE WHICH GENERATED EXCITEMENT ABOUT THE OBESITY COMMUNITY. VERY MUCH LIKE THE HEART WE'RE INTERESTED IN FIBROTIC DISEASE IN ORGANS OF INTEREST TO METABOLIC DISEASE, THE LIVER AN KIDNEY MOSTLY. FINALLY WE HAVE GREAT NEEDS IN THE FIELD OF NEUROIMAGING. TELL YOU JUST A LITTLE BIT ABOUT THAT HOPEFULLY. THERE'S SOME COMMON THEMES. WE ARE A DECADE BEHIND CARDIOVASCULAR IMAGING, FOR INSTANCE. ONE REASON IS BECAUSE THE PHONES WE'RE INTERESTED IN ARE TINY POPULATIONS OF CELLS, VERY DIFFICULT TO IMAGE. THEY REQUIRE MOLECULAR IMAGING IN PARTICULAR. THEY'RE OFTEN DEEP IN THE ABDOMEN WHERE EVERYTHING IS MOVING AROUND. OBESITY, PEOPLE WITH METABOLIC DISEASE ARE OBESE AND MAKES IT MORE DIFFICULT TO IMAGE IN THIS PART OF THE PERSON. MOST TISSUES WE'RE INTERESTED IN ARE FUNCTIONAL IN THE SENSE THAT THEY EITHER SECRETE OR HAVE CHEMICAL FUNCTION. THIS MADE IT A CHALLENGE TO IDENTIFY WITH MOLECULAR IMAGING, BECAUSE YOU HAVE TO USE PROBES THAT DISTINGUISH BETWEEN MASS AND FUNCTION AND THIS IS HARDER THAN YOU OR I WOULD HAVE THOUGHT. WE'RE INTERESTEDDED IN THE ORGANS THAT ACTUALLY FUNCTION CLEAR TRACER SO THIS IS A BIG PROBLEM TO LOOK AT, TINY POPULATION OF CELLS AGAINST A HUGE BACKGROUND. THEY ARE CHRONIC DISEASES SO WE NEED TO MONITOR LONGITUDINALLY IN A SAFE MANNER, WE DON'T WANT TO KILL THE TINY POPULATION OF CELLS WE'RE INTERESTED IN. OUR RESEARCH IMMUNITY IS VERY SOPHISTICATED WHEN IT COMES TO METABOLISM. IT'S GOT LITTLE EXPERTISE WHERE IT COMES TO IMAGING TECHNOLOGY. THIS IS AN ENORMOUS ROADBLOCK FOR US, AS YOU KNOW. EVERY SILOED FIELD OF HE CAN PER TEASE HAS ITS OWN WAY OF THINKING, IN ORDER TO MOVE FORWARD IN IMAGING WE FINE IT DIFFICULT TO FORGE RELATIONSHIPS WHERE PEOPLE SHARE COMMON LANGUAGE AND CAN BE CREATIVE TOGETHER. THIS IS WHERE NIDDK LOOKED FOR RELATIONSHIP WITH NIBIB NOT ONLY IN THE LABORATORY BUT NIH SO WE CAN UNDERSTAND WHERE WE SHOULD BE PUTTING OUR MONEY. AS MENTIONED IN BRIEFIUS TALK THERE'S A BARRIER BETWEEN WORKING WITH ISOLATEDDED ANIMAL -- ANIMAL AND ISOLATED TISSUE MODEL AND GETTING THEM IN THE CLINIC. WE FOUND THIS TO BE REALLY DIFFICULT TO SURMOUNT. I LOOK FORWARD TO A FUTURE WHERE IT'S EASIER TO TESTING CLINICALLY, WE CAN FIGURE IF THINGS ARE SAFE AND MOVE MORE QUICKLY. SO I'M GOING TO START WITH MY FAVORITE IMAGING PANCREATIC BETA CELL. THIS IS A 15 YEAR ENDEAVOR, THESE ARE THINGS THAT WE'RE INTERESTED IN, IT'S NOT JUST AN IDEA OF TRYING TO IDENTIFY THE MASS OF THESE TISSUES THOUGH THAT IS SORT OF GOAL, BIGGEST GOAL. THE REASON AS I MENTIONEDDED BEFORE WE STILL TAUPE KNOW THE NATURAL HISTORY OF THE DISEASE, WE DON'T KNOW IF THE CELLS DIE AND CAUSE DIABETES IN THE BETA CELLS, WE DON'T KNOW IF THEY JUST BECOME „ DYSFUNCTIONAL AND DIE EVENTUALLY AFTER THEY LOSE FUNCTION, THERE IS AN IDEA THAT THEY TRANSDIFFERENTIATE INTO OTHER EYES OF END P KIN CELLS. WE CERTAINLY HAVE NO WAY OF LOOKING AT THAT IN PEOPLE AT THIS POINT IN TIME. ONE WAY WE HOPE TO BE ABLE TO TREAT TYPE 1 DIABETES IS TRANSPLANTATION OF EXOGENOUS CELLS ENGINEERED CELLS OR ISLETS THAT ARE TAKEN FROM CADAVERS, WE WANT TO BE ABLE TO MONITOR THOSE AND -- IN THE PEOPLE THAT RECEIVE THEM. WE'RE VERY INTERESTED IN MONITORING INFLAMMATION TO UNDERSTAND HOW CELL DEATH OCCURS IN DIABETES. BETA CELL FUNCTION IS AN ENORMOUS GOAL BECAUSE WE DON'T HAVE A WAY TO DISTINGUISH FUNCTION FROM MASS IN THE PATHOGENESIS OF DIABETES. WE DON'T KNOW WHEN WE TREAT DIABETICS WHETHER OR NOT WE'RE RESCUING MASS OR IF WE'RE JUST RESCUING FUNCTION OF TINY MASS OF BETA CELLS THAT ARE LEFT. FINALLY WE LOOK TO ANKER RA WE CAN DELIVER THERAPEUTICS TO THE BETA CELL, THIS IS REALLY IMPORTANT BECAUSE WE LOOK AT GROWTH FACTORS YOU DON'T WANT TO DELIVER TO ALL TISSUES. YOU WANT TO GET THEM DIRECTLY TO ISLET CELLS. THIS IS A LON ENDEAVOR. EVERYTHING WE HAVE DONE IN THIS AREA, INCLUDING WORKSHOPS NOW AND FUNDING INITIATIVES HAVE BEEN IN COLLABORATION WITH NIBIB. THIS BROUGHT A TECHNICAL SOPHISTICATION TO ENDEAVOR THAT SIMPLY WOULDN'T BE THERE WITHOUT THIS COLLABORATION. SO A COUPLE OF OF EXAMPLES REAL QUICK TO SHOW YOU WHAT PRODUCTS WE HAVE MADE IN 15 YEARS, WE'RE NOT THERE BUT GETTING THERE. THIS IS A RECENT PAPER A COLLABORATION BETWEEN A SWEDISH GROUP AND LA GROUP. THEY HAVE MANAGED TO TAKE A PROBE THAT WAS DEVELOPED BASED ON DRUG, DEVELOPED FOR IMAGING ING PANCREATIC CANCER AND DEVELOPED TO THE POINT WHERE IT LOOKS LIKE IT MIGHT BE GOOD FOR THE BETA CELL. THE REASON THIS HAS BEEN SUCH A DIFFICULT TASK IS BECAUSE THEY TEND TO BE LARGE LIKE MANY CANCERS, YOU DON'T NEED HIGH SPECIFICITY TO SEE THEM FOR THIS BETA CELL HOWEVER YOU NEED TO INCREASE THE BINDING CONTENT DRAMATICALLY AND YOU NEED A PROBE THAT'S EXTREMELY BRIGHT IN ORDER TO SEE IT. HERE WE HAVE INDICATION WE MIGHT BE GETTING -- I DON'T KNOW HOW TO -- HERE WE GO. YOU CAN BARELY SEE IT BUT THAT HELPS YOU A LITTLE BIT. THIS IS A MONKEY, THIS LABELED PROBE BASED ON DIABETES DRUG HAS BEEN GIVEN AND IT DOES LIGHT UP THE PANCREAS, THIS LITTLE SPOT HERE AND THEY ADDED UNLABELED PROBE TO LOOK FOR BOUNDING SPECIFICITY, YOU CAN SEE THAT LITTLE SPOT DISAPPEARED IF YOU ADDED UP LABELED PROBE, THIS IS THE MAXIMUM INTENSITY PROJECTION. YOU CAN SEE THAT LITTLE NOSE PIECE ON THE GLASS, THOSE ARE THE TWO KIDNEYS THAT DOES FADE AWAY WITH TIME. THIS SHOWS AS YOU ADD INCREASING UNLABELED DRUG, YOU SEE UPTAKE TO PANCREAS GUST GOES DOWN TO NON-SPECIFIC HERE. THIS PARTICULAR PROBE IS NOT TAKEN UP WELL WITH -- BY THE LIVER BECAUSE THAT MAKES IT POSSIBLE TO IMAGE THE PANCREAS. THIS DRUG HAS SOME PROBLEMS. WE DON'T KNOW IF IT'S COMPLETELY SPECIFIC FOR THE BETA CELL UNDER ALL DISEASE CONDITIONS. THOSE THINGS NEED TO BE WORKED OUT. BUT IT IS A GLIMMER OF HOPE THAT WE HAVE THE ABILITY TO SEE THIS TINY NUMBER OF CELLS DEEP IN THE GUT AT LEAST IN ANIMAL MODELS. I THINK I TOLD YOU WHAT WE LIKE TO SEE IS FUNCTION OF THESE CELLS COMPLETELY INDEPENDENTLY FROM MASS OF THESE CELLS. IN ORDER TO UNDERSTAND WHAT'S GOING ON AS PEOPLE BECOME DIABETIC. THIS IS BEAUTIFUL, I'M EXCITED ABOUT THIS, THIS IS FROM DEAN CHERRY'S LAB IN TEXAS, HE'S COME UP WITH A GADOLINIUM BASED T-1 SENSOR THAT'S SENSITIVE. IT TURNS OUT WHEN INSULIN IS SECRETEED FROM THE PANCREAS, IT'S SECRETED WITH A HEFTY LOAD OF ZINC WHICH MANAGES TO STAY LOCAL IN THE CIRCULATION, IT DOESN'T DISSIPATE INTO THE REST OF THE BODY BECAUSE THERE'S UPTAKE TRANSPORTERS IN THAT REGION. THIS MAKES IT POSSIBLE THEN TO ACTUALLY SEE ZINC AS SECRETED WITH THE INSULIN AND USE AS A MARKER. THIS IS A STUDY SHOWING YOU A STUDY DONE IN RATS. THIS IS A NORMAL RAT GIVEN GADOLINIUM MARKER AND THEN GIVEN A BOLUS OF GLUCOSE WHICH CAUSES INSULIN SECRETION. YOU CAN SEE BEAUTIFULLY A FLUSH OF SIGNAL WHERE THE ZINC IS RELEASED AS MARKER FOR INSULIN. IF YOU GIVE A DRUG TO ANIMALS THAT CAUSES THEM TO BECOME DIABETES THAT KILLS THE BETA CELLS, THEY NO LONGER SECRETE INSULIN IN RESPONSE TO GLUCOSE AND YOU SEE THE SIGNAL. WE'RE VERY EXCITED. IT HASN'T MADE IT TO THE -- IT LOOKS LIKE IT MIGHT BE SAFE. THERE'S A HUGE BARRIER GETTING EXCITING PROBES TO HUMAN POPULATIONS AND WE HOPE THIS ONE CAN MAKE IT, CAN BE SHOWN TO BE SAFE TO GO INTO HUMAN POPULATIONS. SO THE NEXT THING I WANT TO TELL YOU ABOUT MOVING AHEAD FAIRLY QUICKLY, WE ARE VERY INTERESTED IN ADIPOSE TISSUE. I SHOW YOU THINGS THAT WE HAVE HAD INITIATIVES IN. JUST TO KEEP THE NUMBER OF INTEREST I SHOW YOU SMALL. WE HAVE HAD ONE WE'RE LOOKING FOR ANOTHER ONE IN OKAY. WE HAD ONE SET OF RFAs. THE REASON PEOPLE ARE INTERESTED IN THIS TISSUE, IT'S CONSIDERED A SIZABLE DRUG TARGET TO TRY TO TREAT OBESITY. THIS IS A TISSUE THAT WEIGHTS ENERGY TO CREATE HEAT. THE IDEA IS IF YOU CAN ACTIVATE THIS TISSUE, YOU MIGHT BE ABLE L TO MAKE THE BODY LESS ENERGY EFFICIENT, BURN OFF MORE CALORIES AND CAUSE WEIGHT LOSS IN PEOPLE. OUR GOAL AT NIDDK TO HELP THIS ENDEAVOR ARE LISTED HERE. WE WANT TO BE ABLE TO PROVIDE TOOLS TO MEASURE THE MASS AND ACTIVITY OF HUMAN ADIPOSE TISSUE THIS IS THE LEVEL WE'RE WORKING ON RIGHT NOW. ONCE WE HAVE THOSE TISSUE TISSUES THOSE TECHNOLOGIES WE WANT TO ESTABLISH THE PREVALENCE OF THIS TISSUE AND PARAMETERS THAT INFLUENCE IT IN A LARGE GROUP OF PEOPLE ACROSS THE NATION. FINALLY, WE WANT TO UNDERSTAND THE PHYSIOLOGICAL OF THIS NEW TISSUE IS. IT'S EXCITING TO HAVE A NEW TISSUE TO WORK ON. THIS IS THE EVIDENCE FROM PET IMAGINING THIS TISSUE EXISTS IN ADULTS. WHICH NOTED THIS IN NEWBORNS, IT'S FOUND ACROSS THE SHOULDER OF NEW BORN THAT GENERATES HEAT AND PEOPLE THINK IT'S MEANT TO KEEP THE NEWBORN WARM AFTER BIRTH. WE DIP THINK IT EXISTED IN ADULTS BUT THIS IS A STUDY SHOWING HOW WE REDISCOVERED IT. THIS IS A LEAN PERSON ROOM TEMPERATURE GIVEN FDG IN PET SCANNER. YOU CAN SEE NOT MUCH GOING ON HERE. IF THAT SAME PERSON IS COOLED DOWN, YOU SEE BILAT L RALLY SYMMETRIC UPTAKE OF GLUCOSE OF THE SHOULDERS AND NECK REGION. THIS IS THE BROWN ADIPOSE TISSUE. IF YOU CHOOSE OBESE PERSON YOU CAN SEE NOT MUCH IS GOING ON UP THERE. SO IT APPEARS THIS IS THE ISSUE THAT'S FOUND MOSTLY IN YOUNGER PEOPLE, LEANER PEOPLE, HIGHLYK INVESTIGATABLE, IT TAKES UP A LOT OF GLUCOSE, THAT'S ALL WE KNOW ABOUT IT AT THIS POINT IN TIME. WHAT WE WOULD LIKE TO BE ABLE TO DO IS HAVE A MEASURE THAT ALLOWS US ONCE AGAIN TO DISTINGUISH BETWEEN MASS OF THE TISSUE AND ACTIVITY OF THE TISSUE. THAT O BOASE PERSON, WE DON KNOW HAS MASS WE CAN'T ACTIVATE TOO COLD THAT COULD BE THE CASE. IF THAT IS THE CASE WE MIGHT BE ABLE TO ACTIVATE THROUGH A DRUG. SO HERE IS A NEW PET PROBE THAT WAS DEVELOPED THROUGH AN R-21 IN THE RFA WE SHARED WITH NIBIB, IT IS BASICALLY A TARGET TRANSPORTER IN THE HOPES THAT THIS WOULD GIVE US A BETTER SENSE OF MASS WITHOUT HAVING TO ACTIVATE TISSUE. YOU CAN SEE THIS IS AN FDG EXPERIMENT OF A RAT. THIS IS THAT SAME RAT IN THE COLD. WHAT YOU CAN SEE IS RIGHT HERE, YOU SEE SOME LIGHTING UP OF THE BROWN ADIPOSE TISSUE. HERE IS THIS NEW TRACER AND YOU CAN SEE THAT EVEN IN WARM CONDITIONS, YOU CAN LIGHT UP THE BROWN ADIPOSE FISH THE SHOE AND IT DOESN'T CHANGE COLD STRESS. THIS IS A COMPETITION EXPERIMENT WITH COLD TRACER TO SHOW YOU IT IS QUITE SPECIFIC. SO THIS IS THE KIND OF THING WE'RE LOOKING FOR. WE WOULD LIKE TO MY MIND IF WE CAN FINE AN MR TRACER IT MIGHT BE BETTER BECAUSE THIS IS A PRETTY SUBSTANTIAL PIECE OF TISSUE, WE TOP NEED HIGH SENSITIVITY OF PET BUT IT WOULD BE NICE TO HAVE AN MR TRACER THAT WE CAN USE IN A NON-RADIO ACTIVE MANNER TO DO A LARGE EPIDEMIOLOGICAL TRIAL ACROSS HUNDREDS OF PEOPLE ACROSS THE COUNTRY. THERE'S ANOTHER CHALLENGE, THIS STORY IS DEVELOPING QUICKLY, THERE'S A LOT OF INTEREST, IT TURNS OUT THAT THESE TISSUES ARE VERY, VERY PLASTIC. THAT YOU CAN ACTUALLY HAVE CONVERSION OF TYPICAL WHITE ADIPOSE TISSUE THAT YOU FIND ALL OVER YOUR PERIPHERY INTO SOMETHING THAT LOOKS VERY MUCH LIKE BROWN ADIPOSE TISSUE. BUT JUST IN A FEW CELLS IN A LARGE WHITE DEPOT ALL OVER THE BODY, AND THIS TRANSDIFFERENTIATION IS PROVOKED BY COLD EXPOSURE, BY EXERCISE, IT'S PROVOKED BY OTHER KINDS OF SYMPATHETIC STIPULATION, IT'S QUITE EXCITING BECAUSE THIS IS THE SORT OF THING THAT MIGHT GIVE ENOUGH TISSUE TO COMBAT OBESITY IF WE CAN ACTIVATE IT BUT WE DON'T KNOW HOW TO IMAGE IT OR TELL HOW MUCH IS THERE IN ANY GIVEN INDIVIDUAL. SO WE REALLY DO NEED A HIGHLY SPECIFIC IMAGING TECHNIQUE TO ROOK AT THE PERIPHERY NOW AND PEOPLE AND TRY TO UNDERSTAND THIS NEW TISSUE. FIBROSIS, WE HEARD ABOUT THIS, FROM OUR CARDIOVASCULAR TALK AND WE HAVE THE SAME NEEDS IN INTERNAL ORGANS. OUR FLAGSHIP NEED IS TO IMAGE FIBROSIS IN THE LIVER. THIS IS IMPORTANT BECAUSE IT'S AN IMPORTANT MECHANISM THAT SEEMS TO CAUSE PROGRESSION OF FATTY LIVER DISEASE WHICH HAS BECOME SO WIDESPREAD NOW WITH OUR OBESITY EPIDEMIC THAT IT SEEMS TO BE AFFECTING ABOUT 30% OF THE PEOPLE IN THIS COUNTRY. FATTY LIVER DISEASE CAN PROGRESS ON TO GNASH, NON-ALCOHOLIC HEPATOSIS AND KEEP PROGRESSING TO CIRRHOSIS AN ACTUALLY ENUP IN LIVER FAILURE THAT WOULD REQUIRE LIVER TRANSPLANTATION. WE WOULD LIKE TO BE ABLE TO UNDERSTAND THE PROGRESSION OF THIS DISEASE IN ORDER TO IDENTIFY THOSE PEOPLE THAT ARE LIKELY TO GO ON TO CIRRHOSIS. SO WE HAVE HAD COUPLE OF WORKSHOPS, AND ARE PLANNING ANOTHER FOR 2014 AND SEVERAL INITIATIVES. RIGHT NOW WE'RE PUTTING ORGANS, KIDNEY PROSTATE BLADDER UPPER URINARY BONE TRACT AND BONE MARROW. THE GOALS FOR RESEARCH WOULD BE TO UNDERSTAND HOW PATHOLOGICAL FIBROSIS THAT LEADS TO ORGAN FAILURE, IS DIFFERENT FROM THAT, JUST SEEN IN NORMAL AGING. WE NEED TO CORRELATE THE STAGE OF FIBROSIS WITH DISEASE PROGRESSION AND ORGAN DYSFUNCTION, AGAIN IN MANY CASES WE DON'T KNOW A LOT ABOUT THE PATHOGENESIS OF THESE DISEASES. AND FINALLY MONITOR RESPONSE TO THERAPY IN ANY GIVEN PATIENTS. WE HAVE AN EMERGING MR TECHNIQUE FOR LOOKING AT FIBROSIS IN THE LIVER. AS YOU CAN SEE, I WAS REALLY QUITE IMPRESSED TO SEE THIS WORK WAS DEVELOPED USING NIBEB GRANT IN MAYO CLINIC. THIS WENT FROM RESEARCH PROJECT TO CLINICAL USE IN SOMETHING LIKE FIVE YEARS SO THIS ENDED UP BEING A VERY IMPORTANT TECHNOLOGY, THAT WE START SEEING SPREAD MOREICALLY NIX OVER THE NEXT FEW YEARS SO HERE IS EXPERIMENT IN A PATIENT WITH EARLY FIBROSIS FATTY LIVER PROGRESSING TO DISEASE. AS I CAN SEE EARLY STIFF, IT'S FLEXIBLE, YOU CAN SEE THAT BECAUSE IT'S DARK COLORS HERE. THIS IS THE LIVER. THE STIFFNESS HAS BECOME EXTREME. THIS LIVER IS STIFF AND BRITTLE, ESSENTIALLY TELL THE CONFERENCE BETWEEN TWO SETS OF PATIENTS. THIS IS NICE BECAUSE IT'S NOT INVASIVE, IT'S NICE BECAUSE WE GET TO MAP AND LIVER SOMETHING WE CAN DO WITH BIOPSY WHICH IS THE GOLD STANDARD FOR DIAGNOSING THIS DISEASE, CORRELATES OKAY WITH HISTOLOGY, YOU CAN TELL THE DIFFERENCE BETWEEN EARLY AND LATE FIBROSIS. BUT IT'S NOT PERFECT, IT'S NON-SPECIFIC, NON-QUANTITATIVE, IT DOESN'T TEACH AS MUCH ABOUT PATHOGENERAL AS WE WOULD LIKE. IT PROBABLY IS NOT GOING TO BE PERFECT FOR THE OTHER ORGANS OF INTEREST. SO WHAT WE'RE LOOKING FOR IS SPECIFIC MOLECULAR IMAGING PROBES. THIS IS ONE THAT JUST CAME OUT OF JOHNS HOPKINS, PETER CARAVAN'S LAB. JUST TO MOVE VERY QUICKLY, YOU CAN SEE MORE COLOR IN THIS MOUSE TREATED WITH CARBON TETRA CHLORIDE TO GENERATE FIBROSIS. I WILL SKIP QUICKLY TO MY LAST NEED, THAT'S NEUROIMAGENING OBESITY AND DIABETES RESEARCH. WE HAD A WORKSHOP AN INITIATIVES IN THIS AREA. OUR GOALS ARE REALLY TO UNDERSTAND THE ROLE OF THE BRAIN AN HUMAN OBESITY PATHOGENESIS AND THAT'S MOSTLY EATING BEHAVIOR AND THE CONTROL OF ENERGY HOMEOSTASIS. WE WANT TO UNDERSTAND P EFFECTS OF OBESITY AND DEE BEE TEASE ON THE HUMAN BRAIN INCLUDING COGNITION, WE WANT TO UNDERSTAND THE MECHANISMS FOR WHAT WE CALL HYPERGLYCEMIA UNAWARENESS IN DIABETES, WHEN A DIABETIC BECOMES HYPOGLYCEMIC OFTEN HE CANNOT RECOGNIZE THAT BASICALLY HE DOESN'T BECOME HUNGRY OR AGITATED THE WAY A NORMAL PERSON WOULD AND THEREFORE EAT AND CORRECT THE HYPERGLYCEMIA. ANYBODY WHO READ IT IS LITERATURE IS AWARE THE NUMBER OF STUDIES THAT WENT FROM APPROXIMATELY ZERO, 5, 6, YEARS AGO TO HUNDREDS NOW. THIS IS A REALLY EXCITING AREA, BUT IT'S DOMINATED BY FMRI RIGHT NOW. AND THAT'S BECAUSE WE'RE EXPLORING NETWORKS INVOLVED. WE ARE DOING THE EXPLORE TORE RESEARCH ON WHAT I THINK MORE RESEARCH WILL BE DONE IN THE FUTURE. THAT'S GOING TO INCLUDE THESE THINGS. HORMONE RECEPTOR DENSITY AND FUNCTION IN THE HUMAN BRAIN, THERE'S HORMONES GENERATED FROM OTHER PARTS OF THE BODY, THAT TELL THE BRAIN THE STATE OF ENERGY BALANCE. A LOT OF THESE EXPERIENCE WHAT WE CALL RHESUS TAN. INSULIN RESISTANCE OR LEPTON RESISTANCE ARE WELL KNOWN. MANY OTHER HORMONES EXPERIENCE IT TOO AND WE WANT TO LEARN THE NATURE OF THIS IN PEOPLE. NEW TRANSSENSING, THIS IS ALTERED IN DIABETES AND ANIMAL MODELS, WE WANT TO STUDY IT IN PEOPLE. HYPOTHALAMIC NEUROTRANSPORTERS AN RECEPTORS BECOME BETTER UNDERSTOOD IN ANIMAL MODELS, WE NEED TO MOVE TO PEOPLE. THE SITE OF OBESITY DRUGS, THIS IS IMPORTANT BECAUSE MANY HAVE UP PLEASANT SIDE EFFECTS. ATYPICAL ANTIPSYCHOTICS CAUSE OBESITY SO MANY PATIENTS TREATED WITH WITH PSYCHIATRIC DISEASES BECOME OBESE AND THERE IS SOME PHYSIOLOGIC MECHANISM, WE DONE UN. FINAL PLY THE LINKS BETWEEN DIABETES AND DEMENTIA. SO I HAVE A BIG WISH LIST OF IMPROVE TECHNOLOGIES THAT REALLY GOING TO BE REQUIRED IN ORDER TO BE ABLE TO BRING MOLECULAR IMAGING TO FULL PLAY. AND THE RESEARCH AND THE CLINIC IN TERMS OF METABOLIC DISEASES. I THINK IT'S A WISH LIST THAT BASICALLY DR. MEDIGREW SAW WE COULD PUT TOGETHER TEN YEARS AGO. IT HASN'T CHANGED. WE HAVE GOTTEN BETTER BUT NOT WHERE WE NEED TO BE YET. SO I WOULD LIKE TO THANK YOU VERY MUCH FOR THIS OPPORTUNITY. [APPLAUSE] >> THANK YOU. YOU MAKE AN EXCELLENT CASE FOR COLLABORATIONS BETWEEN DISCIPLINES AN INSTITUTES. OUR NEXT SPEAKER IS DR. KIRK FREY FROM THE UNIVERSITY OF MICHIGAN, HE'LL BE TALKING ON MOLECULAR]Mq IMAGING NEEDS AND TRANSLATIONAL AND CLINICAL NEUROSCIENCE. WELCOME. >> THANK YOU. THIS IS A RATHER TALL ORDER. AND I HOPE NOT TO GO OVER TIME SO SOME OF THIS MAYBE A LITTLE MORE EXECUTIVE THAN I INTENDED. I HAVE AT THIS CLOSURES. I DON'T THINK ANY WILL HAVE ANYTHING TO DO WITH WHAT WE'RE GOING THE TALK ABOUT. WHAT I WANT TO START WITH IS THE BIGGEST AREA OF IMPACT IN DEGENERATIVE DEMENTIA IS AN EMERGING EPIDEMIC AMONG HUMANS. THERE ARE TWO AREA FOR MOLECULAR IMING THAT WILL HAVE POTENTIAL SIGNIFICANT IMPACT IN OUR ABILITY TO DISCOVER NEW TREATMENTS FOR THIS PROBLEM. FIRST IS ENDOPHENOTYPE PATIENTS. THIS I BELIEVE IS A NECESSITY IN TERMS OF DISCOVERY OF NEW EFFECTIVE THERAPIES. SECOND IS TO ALLOW EFFICIENT EVALUATION POTENTIAL NEW TREATMENTS, WE NEED DISEASE PROGRESSION BIOMARKERS THAT WILL ADVANCE US DETERMINING WHAT TREATMENTS LOOK FAVORABLE EARLY ON WITH SMALL NUMBER OF SUBJECTS. THE PROBLEM THAT WE HAVE IN MOST NEURODEGENERATIONS IS ARTICULATED HERE IN THIS VIN DIAGRAM. NEURODEGENERATIVE PROBLEMS ARE SYNDROMES, NOT NECESSARILY DISEASES, AND PATHOLOGISTS ARE ABLE TO TELL US EXACTLY WHETHER A PATIENT HAS BASED ON POSTMORTEM ANALYSIS OF ACCUMULATION OF PATH LOGICAL PROTEIN AGGREGATES SO HERE IS A BETA PAP DID IN AMYLOID DEPOSITIONS, HERE ARE ABNORMALITIES THAT HAVE PROTEIN IN AGGREGATES AND HERE ALPHA SYNUCLEIN. BASED ON THESE THREE, PROBABLY 85% OF NEURODEGENRETIVE DISEASES CAN BE CHARGE RISED SO A BETA AMYLOID WITH KNEW FIBRILLARY TANGLES OF TAU IS THE HISTOLOGICAL TESTIFY ANYTHING OF AL ALZHEIMER'S DISEASE. THERE'S TAU ONLY DISORDERS FRONTAL TEMPORAL DEMENTIA THOUGH HALF RELATE NOT TO TA, DEPOSITION BUT OTHER PROTEINOPATHYS NOT DEPICTED HERE. AND CORTICO BASAL GANGLIONIC DEGENERATION. IN THE SYNUCLEINOPATHYS WE HAVE PARKINSON AND THE LESS MULTIPLE SYSTEMS ATROPHIES BUT THESE ARE ACCUMULATIONS OF THE PROTEIN ALPHA SYNUCLEIN. DEMENTIA WITH LOUIS BODY IS OVERLAP BETWEEN PARKINSON AND AMYLOID DEPOSITION SO AMYLOIDOSI IS IN TWO-THIRDS OF PATIENTS BUT THEY'RE ALL SHOWING DEPOSITIONS OF ALPHA SYNUCLEIN AND PARKINSON DISEASE AS WELL. THEN UNCOMMON, MAYBE 15% OF DLB PATIENTS WHO HAVE WHAT'S CALLED THE LOUIS BODY VARIANT OF ALZHEIMER'S DISEASE AND THEY MEET ALL THE NECESSARY CRITERIA FOR AD BUT THEY ALSO HAVE LOUIS BODY DEPOSITION SUCH AS MEET THE DEFINITION OF PARKINSONISM. SO THIS IS THE COMPLEXITY WE'RE FACED WITH IN TERMS OF THE ACTUAL DIAGNOSIS OF A PATIENT BY PATHOLOGIST AMER AND CLINIC WHETHER DEMENTIA OR MOVEMENT AT THIS ORDERS THE ACCURACY OF CLASSIFYING A PATIENT IN FRONT OF US IS 70 TO 80% SO WE MISS IT A QUARTER TO THIRD OF THE TIME. THIS AS YOU MAY IMAGINE IS A BIG PROBLEM WITH REGARDS TO GOING FORWARDS AND DEVELOPMENT OF NEW DRUGS YOU WANT TO EMPLOY WHEN A PATIENT IS FIRST SYMPTOMATIC, NOT PATHOLOGIST. SO LET'S SKIP THIS IN THE INTEREST OF TIME, THIS IS A HUGE PROBLEM FOR US AND IT'S MOUNTING BECAUSE THE POPULATION IS AGING. LET ME TALK ENDOPHENOTYPING AND DEMENTIA, THIS COMES FROM OUR LABORATORY BUT I THINK IT IS READILY TRANSLATEABLE DEPENDING UPON INSURANCE COVERAGE BECAUSE MARKERS WE USE HAVE FDA APPROVED LIGANDS THAT THAT COULD BE SUBSTITUTED HERE. SO WHAT WE DID IN CLINIC IS WE TOOK 75 PATIENTS WITH MILD EARLY DEMENTIA, AND CLASSIFIED THEM ACCORDING TO STANDARD OF PRACTICE AND WE ACHIEVED A CLINICAL CONSENSUS DIAGNOSIS AMONG THREE DEMENTIA EXPERTS WHAT EACH INDIVIDUAL PATIENT HAD AS THEIR REASON FOR COGNITIVE DECLINE N. PARALLEL WITH THIS, OF COURSEEN DISCLOSED WE DID NEUROIMAGING FOR AMYLOID DEPOSITION AND FOR STRIATAL DEGENERATION. HERE IS THE PHENOTYPING THAT WE WOULD DO BASED ON IMAGING. SO ALZHEIMER'S DISEASE HAS A STRONG AMYLOID SIGNAL, NORMAL STRIATAL TERMINALS. DEMENTIA WITH HUEY BODIES HAS NO AMYLOID AS IN THIS CASE BUT IT CAN BE AMYLOID POSITIVE AS MENTIONED EARLIER. BUT ALL INDIVIDUALS HAVE A SEVERE NIGRAL STRIATAL LESION AS DEPICTED IN THIS CARTOON, THEN FRONTAL TEMPORAL DEMENTIAS WHO NEVER HAVE AMYLOID AND WHO USUALLY HAVE VERY SUBSTANTIALLY INTACT STRIATAL PROJECTION. SO THE QUESTION IS, HOW DOES THE CLINICAL CLASSIFICATION PREDICT OR NOT PREDICT MOLECULAR CLASSIFICATION? AS YOU CAN SEE HERE, DOWN THE DIAGONAL ARE PATIENTS WHO WERE CLASSIFIED IDENTICALLY BY THE CLINICAL CONSENSUS VERSUS NEUROCHEMICAL ENDOPHENOTYPING. YOU CAN SEE FULLY 35% INDIVIDUAL PATIENTS WERE MISS CLASSIFIED BY ONE OR THE OTHER OF THESE SCHEMA S AND WE BELIEVE NEAR IMAGE PHENOTYPING IS MORE ACCURATE AND FOLLOWING TO AUTOPSY SO SEE IF THAT'S THE CASE. IF I'M A DEVELOP DEVELOPERS AND I WANT TO INTERVENE PATIENTS WITH EARLY STAGE DEMENTIA, A THIRD OF THE PATIENTS DON'T HAVE THE UNDERLYING CONDITION I TARGETED. THIS IS A TERRIBLE PROBLEM WITH REGARDS TO REJECTION OF POTENTIALLY THERAPEUTIC NEW APPROACH. WE EXTENDED FURTHER INTO PATIENT WHOSE HAVE WHAT'S CALLED MILD COGNITIVE IMPAIRMENT, THIS IS BELIEVED A PRECURSOR TO DEMENTIA IN MANY INSTANCES AN OVER A FIVE YEAR PERIOD, SOMETHING LIKE TWO-THIRDS, THREE QUARTERS OF PATIENTS, WITH MILD COGNITIVE IMPAIRMENT EVOLVE CLINICALLY TO ACHIEVE A DIAGNOSIS OF DEMENTIA. THIS IS THE STAGE WHERE WE WOULD REALLY LIKE TO INTERVENE WITH A DISEASE MODIFYING APPROACH AND STABILIZE THE PATIENT WHILE STILL QUITE FUNCTIONAL. TO MAKE A LONG STORY SHORE WE APPLIED THE SAME APPROACH I JUST SHOWED YOU WITH MILD DEMENTIA. AND HERE, WE FIND AMNISTIC MILD COGNITIVE IMPAIRMENT, BELIEVE AD PRECURSOR IN THE MAIN FOR ALZHEIMER EAR DISEASE DID NOT CAPTURE MAJORITY OF PATIENTS WHO HAD NEUROIMAGING CLASSIFICATION CHARACTERISTIC OF ALZHEIMER'S WITH AMYLOID DEPOSITION. SO THERE ARE OTHER COGNITIVE IMPAIRMENT AS PREDICTIVE OR MORE OF THE DEVELOPMENT OF ALZHEIMER'S DISEASE AND WE WOULD NOT HAVE TARGETED THEM PROPERLY. SIMILAR HARLEY IF WE USED MEMORY DEFICIENT MILD COGNITIVE IMPAIRMENT AS IDENTIFIER WHO HAS NASCENT ALZHEIMER'S DISEASE THOUGH THE NUMBERS ARE SMALL YOU CAN SEE WE IDENTIFIED ONE OUT OF SEVEN INDIVIDUALS WHO DIDN'T HAVE AMYLOID AT ALL AND FRONTAL TEMPORAL DEMENTIA INSTEAD. NOW, HOW RELEVANT IS THIS APPROACH AND IS IT IMPORTANT TO KNOW WHAT PATIENTS HAVE BEFORE THEIR DEMENTIA IS WELL DEVELOPED AND MANIFEST? THE ANSWER IS WELL, WE THINK THAT IT IS. SO THAT'S GREAT INDUSTRY INTEREST IN THE PHARMA INDUSTRY, TARGETING THE AMYLOID CASCADE PATHWAY IN AL HIGH MR. CXFC -- DISEASE, ANTI-AMYLOID TREATMENTSI-„ WILL IN FACT BE PREVENTIVE AGAINST DETERIORATION IN ALZHEIMER'S DISEASE. TO SUMMARIZE A LOOT OF TRIALS SOME WHICH ARE STILL UNDERWAY, THE ANSWER IS APPARENTLY NOT. ONCE A PATIENT IS DIMEANTED EFFECTIVE REMOVAL OF AMYLOID FROM THE BRAIN APPEARS NOT TO STOP PROGRESSION OF SYMPTOMS AND SUBSEQUENT NEUROLOGIC DEGENERATION. SO THE IDEA THAT WE HAVE EMERGING IS THIS, ILLUSTRATED IN THIS CARTOON, AMYLOID DEPOSITION IS AN EARLY FEATURE OF THE ALZHEIMER'S AMYLOID INITIATED CASCADE PATHWAY PERHAPS ANTICIPATING EVOLUTION OF SYMPTOMS A Z MUCH AS A DECADE AS DEMON P STRAITED IN MONOGENETIC ALZHEIMER'S DISEASE POPULATIONS. THE PRESENCE OF THE AMYLOID THOUGH IS ASSOCIATED WITH DEVELOPMENT, THE TA, RELATED NEUROFIBRILLARY PATHOLOGY ASSOCIATED WITH DEVELOPMENT OF NEUROLOGIC SYMPTOMS AN DETERIORATION OF FUNCTION. WE DO KNOW THAT ONCE THESE SIP TOMS HAVE ARISEN ANTI-AMYLOID THERAPY APPEARS NOT TO HAVE THE EFFICACY WE WOULD LIKE. SO THE IDEA NOW IS OKAY, THE YOU'RE GOING THE TARGET THE AMYLOID CASCADE PATHWAY MOVE INTO THIS REALM OF PATIENTS WHERE PATIENTS ARE ASYMPTOMATIC OR MILDLY SYMPTOMATIC, AND THIS IS GOING TO BE YOUR POINT OF INTERVENTION, CLINICALLY WE HAVE NOT A CLUE HOW TO FIND PATIENT WHOSE HAVE THIS PROBLEM AND SEPARATE THEM FROM THOSE THAT HAVE SOMETHING ELSE. AMYLOID IMAGING CAN DO THIS AND THIS IS AN ILLUSTRATION HOW MOLECULAR ENDOPHENOTYPING MAYBE CRITICAL TO THE DEVELOPMENT OF NEW THERAPIES. SO LET ME MOVE HERE. TO TAKE THIS FURTHER WE NEED TO LOOK AT WHAT WE HAVE AND WHAT WE LACK AT THE PRESENT TIME. SO WITH REGARD TO THIS ENDEE PHENOTYPING WE HAVE 18 FDG I DIDN'T TALK BUT NICELY ABLE TO CLARIFY FOR US WHO HAS UNDERLYING NEURODEGENERATION VERSUS WHO MAY BE DEPRESSED OR SYMPTOMATIC BUT WITHOUT NEURODEGENERATIVE CAUSE. WE HAVE FROM DR. MATHIS, NUMBER OF AGENTS ABLE TO DEPICT THE DEPOSITION OF FIBRILLARY AMYLOID AND THAT OF CURSE IS A NECESSITY TO MAKE THE DIAGNOSIS OF ALZHEIMER'S AND THE DEPOSITION APPEARS TO BE PRESENT EARLY ENOUGH IN THE EVOLUTION THAT IT MIGHT NICELY SERVE AS A BIOMARKER WE CAN USE THE TARGET EARLY ANTI-AMYLOID INTERVENTIONS. I THINK THIS LIKELY IS TO OCCUR IN THE NEAR FUTURE. THERE ARE ALSO MARKERS OF THE STRIATAL PATHWAY, I SHOWED IN MY LAB, THERE ARE AGENTS INCLUDINGD DOES FDA APPROVED IL-23 USED TO DEPICT THE SAME PATHOLOGY. WHAT WE DO NOT HAVE THOUGH, LET'S PRESUME WE HAVE THE TOOLS TO INVESTIGATE MORE AGGRESSIVE EARLY INTERVENTION IN ALZHEIMER'S AN AMYLOIDOPATHYS. WHAT WE DO NOT HAVE IS AN EFFECTIVE APPROACH THE OTHER DEMENTIAS DEPICTED. AND IN PARTICULAR FRONTAL TEMPORAL DEMENTIA IS NOT A SINGLE ENTITY, IT'S FRONTAL TEMPORAL DIMENSIONS, PERHAPS HALF HAVE A TAU BASED PATHOLOGY BUT OTHERS HAVE DEPOSITIONS OF PRO GRAND LYNNE, THERE ARE GENETIC CAUSES GDP 43 AND C-9 ORF THAT APPEAR RELATED TO REGULATION OF RNA TRANSCRIPTION OR AT LEAST OPERATE AT THAT LEVEL. IF WE WANT EFFECTIVE TREATMENT FOR TAU BASED FRONTAL TEMPORAL DEMENTIAS, MANY APHASIA PATIENTS AN FRONTAL TEMPORAL DEMENTIAS, HALF OF THEM, WE WOULD NEED TO KNOW THEY HAVE TAU OPPOSED TO ONE OTHER ETIOLOGIES IF THERE'S GOING TO BE A TAU BASED APPROACH. AN IMPORTANT RECOGNITION HERE IS THIS TAU AND FRONTAL TEMPORAL DEMENTIA IS NOT THE SAME IN NEUROFIBRILLARY TANGLES. SO IT'S AGGREGATE STRUCTURE IS CONSIDERABLY DIFFERENT. AMONG ALL THE TAUOPATHYS, THERE ARE DIFFERENT PRIMARY STRUCTURES THAT AGGREGATES. SO IT MAYBE THAT THE PROBE THAT TELLS US ABOUT NEUROFIBRILLARY TANGLES AND ALZHEIMER'S IS NOT ONE THAT TELLS FRONTAL TEMPORAL DEMENTIAS IN OTHERi/K AMORPHOUS TAU DEPOSITIONS, FURTHER PROBE AND INVESTIGATION WILL BE EFFECTIVE FOR US. WITH REGARDS TO MOVEMENT DISORDER DEGENERATIONS AN ENDOPHENOTYPE APP TYPING A SIMILAR NEED ARISES. WE CAN TELL BASED ON AVAILABLE PROBES ANOTHER NIAGRAL STRIATAL PATHWAY WHICH HAVE DEGENERATION OF SUBSTANTIA NIGRA AND NEURODEGENERATIVE CAUSE FOR THEIR MOVEMENT DISORDER. BUT WHAT WE CAN'T DO IS ACCURATE LY DISTINGUISH AMONG THOSE DISORDERS THAT HAVE ALPHA SYNUCLEIN DEPOSITIONS WHICH ARE PARKINSON DISEASE AND MULTIPLE SYSTEMS ATROPHY, VERSUS THOSE THAT ARE TAU DEPENDENT WHICH IS PROGRESSIVE SUPER NUCLEAR PALSY AND CORTICAL BASAL DEGENERATION. SO PARKINSON DISEASE IS BY FAR THE MOST COMMON BUT THESE OTHER DISORDERS HAVE NO TREATMENT WHATSOEVER AND AGAIN, TO DISCOVER ONE, IT WILL BE NECESSARY TO KNOW EARLY IN THE EVOLUTION OF THEIR PROBLEM THAT THEY DON'T HAVE PARKINSON DISEASE, DO HAVE ONE OF THESE OTHER ENTITIES, AND P TO USE THIS ENDOPHENOTYPING TO MAP IN THE CLINICAL TRIAL. WHAT ABOUT PROGRESSION BIOMARKERS? WHAT WE ARE RELIANT UPON P AT PRESENT IN TERMS OF EVALUATING POTENTIAL DISEASE MODIFYING THERAPIES IS END OUTCOME, THE CLINICAL MANIFESTATION OF DISEASE PROGRESSION AND HAVE I IN SOME WAY CHANGED THAT. THIS IS OF COURSE WHAT WE HAVE TO HAVE FOR AN EFFECTIVE THERAPY THAT MODIFIES DISEASE COURSE BUT UNEFFICIENT IN TERMS OF LACK OF PRECISION IN MOST CLINICAL MARKERS AND THEREFORE THE NEED FOR LARGE NUMBER OF PATIENTS FOLLOWED OVER A LONG PERIOD OF TIME. BY P THE WAY, ONE NEEDS TO EXCLUDE THE POSSIBILITY THAT YOUR INTERVENTION HAS HAD A SYMPTOMATIC, NOT DISEASE MODIFYING EFFECT. SO WHAT DO WE HAVE FOR ESTABLISH BIOMARKERS OF DISEASE PROGRESSION? VIRTUALLY NOTHING. WHAT DO WE NEED? WE NEED TRACERS THAT ARE OBJECTIVE MEASURES OF VULNERABLE NEURONS AND THEY'RE INTEGRITY. AND IN PARTICULAR, GLUTAMATE NEURONS WE HAVE VIRTUALLY NOTHING. DOWN MEAN NEURONS WE HAVE MARKERS BUT NOT VALID BIOP MARKERS FOR DISEASE AS OF YET, ACETYLCHOLINE SEROTONIN AND OTHERS KNOWN VULNERABLE IN THESE DEGENERATIONS. SO THIS IS AN AREA WITH WE MAY NOT HAVE THE TRACER IN HAND BUT WE DON'T HAVE THE DATA TO ESTABLISH AS VALID PROGRESSION BIOMARKERS. TWO OTHER AREAS I WANT TO TALK ON AND HOPEFULLY SAVE TIME WE CAN HAVE SOME QUESTIONS AND BRIEF DISCUSSION. NEUROINFLAMMATION I AN DR. MATHIS TARGETED AS IMPORTANT FOR FURTHER CONSIDERATION, I'M GOING TO TOUCH ON THIS ONLY BRIEFLY. NEUROPLAINMATION IS A COMPLICATED CASCADE OF PHYSIOLOGIC AND SOMETIMES PATHOLOGIC PROCESSES. FUNDAMENTALLY THERE'S VASCULAR CONTRIBUTIONS, THISND INCLUDES INCREASED BLOOD BRAIN BARRIER PERMIBILITY AN REACTIVE HYPOEMIA AS WELL THOUGH THE BRAIN IS A WELL PROFUSED ORGAN ABSENT INFLAMMATORY CHANGE. THERE'S CELLULAR CONTRIBUTIONS. THESE ARE LARGELY EXOGENOUS, THAT IS MIGRATION SPECIFIC LEUKOSITES TYPE THE BRAIN WHICH ARE WE THINK RECRUITED CHEMOTACTICALLY, THERE ARE A NUMBER OF ENDOGENOUS SIGNALSES AND/OR REACTIONS, THIS INCLUDE STIMULATION OF QUIESCENT MICROGLIA, SO THEY'RE ACTIVATED. THERE'S REACTIVE GROWOSIS BY WHICH -- GLIOSIS, CHANGES IN ASTROCYTES AND P INTERSTITIAL CELLS WITHIN THE BRAIN THEY PEER WHEN INFLAMMATION IS PRESENT. IN THEORY WE HAVE NICE POTENTIAL TARGETS IN ALL THE AREAS BUT IN PRACTICE THEY'RE DISCOVERED NOT NECESSARILY FOR THIS PURPOSE AND RELATIVELY POORLY UNDERSTOOD IN TERMS OF WHAT THEIR SALIENCE REALLY IS. BUT IN TERMS OF BLOOD BRAIN BARRIER DISRUPTION, WE HAVE IN METASTASIS WAYS TO DETERMINE THIS, INCLUDING GADOLINIUM ENHANCED MRI AND POSITRON TOMOGRAPHY METHODS WITH SIMILAR TRACERS THAT ARE MORE SENSITIVE. INFLAMMATORY CELLULAR RESPONSE, THIS SAN INTERESTING AREA THAT HASN'T BEEN BIOCHEMICALLY PURSUED VERY AGGRESSIVELY. BUT IT TURNS OUT THAT THE TRACER OF ALPHA METHYL TRIPTOFAN WHICH WAS DEVELOPED INITIALLY TO MAP SEROTONIN BIOSYNTHESIS IS VERY EFFECTIVELY TRAPPED IN ASSOCIATION WITH AREAS WHERE THERE'S AN INFILTRATION OF MONONUCLEAR WHITE CELLS FROM SYSTEMIC CIRCUMSTANCE LACE. BECAUSE AMT IS METABOLIZED NOT JUST IN THE SEROTONIN PATHWAY BUT ACTUALLY METABOLIZE TOE (INDISCERNIBLE) ACID RETAINED LONG TERM IN THE BRAIN AREA AND ACTUALLY IS AN P EXCITE TOE TOXIN SO GIVES RISE TO EXPECTLATION WHY ARE CERTAIN INFLAMMATORY LESIONS DELETERIOUS TO SURROUNDING NEURONS, IT COULD BE EXCITE TOXICITY AND WHY CERTAIN INFLAMMATORY FOCI EPILEPTOGENIC, COULD BE BECAUSE OF THE THE PATHWAY. THIS IS NOT EXSENTIVELY EVALUATED. IN TERM OF REACTIVE ASTRO CYTOSIS, THE ONLY THING IN THE CURRENT TOOLBOX IS IMAGING OF MONOAMINE OXIDASE B, REACTIVE ASTROCYTES EXPRESS HIGHER CONCENTRATION OF MAOB AND CARBON 11, AN ESTABLISHED MARKER OF MAOB, IT DOES NOT HAVE PARTICULARLY OPTIMAL KINETIC PROPERTIES, ITS USE LIKELY TO BE MARGINAL IN TERMS OF SENSITIVITY AND SPECIFITY. THERE'S A TARGET THAT ACHIEVED A LOT OF INTEREST LATELY, THE MITOCHONDRIAL TSPO. USED TO BE REFERRED TO AS THE PERIPHERAL BENZODIAZEPINE RECEPTOR. AND INITIAL LIGAND WAS CARBON 11 LABELED PK 11195, VERY LIMITED KINETIC PROPERTIES, AND SUBOPTIMAL FOR THIS. THERE ARE A WHOLE POST OF SECOND AND THIRD GENERATION TRACERS, DEVELOPED BY DR. ENNIS, INTRAMURAL PROGRAM CALLED PDR-28. WE DON'T KNOW ABOUT THIS PARTICULAR SOLITARY TARGET WHAT ITS RELATIONSHIP IS BETWEEN ACTIVITY AND INFLAMMATORY PROCESS VERSUS BINDING OF THIS AGENT. SO IN SUMMARY, THIS AREA, WE HAVE A NUMBER OF OARs IN THE WATER IF YOU WILL, SIMILAR OR DISSIMILAR ASPECTS OF LEAGUES AND VERY INTERESTING HOW THEY RELATE TO ACUITY AND EVOLUTION OF INFLAMMATORY PROCESS. I THINK THESE ARE ALL CRITICAL TO BETTER UNDERSTANDING OF THE NEUROINFLAMMATORY PROCESS AND ALSO DO MANY DISEASES THAT HAVE INFLAMMATION AS A PORTION AS OPPOSED TO MAYBE PRIMARY FOCUS. THE LAST THING I WANT TO LEAVE US WITH IS AN AREA THAT IS LARGELY IN BEHAVIORAL NEUROLOGY, PSYCHIATRY AND OTHER BEHAVIORAL DISORDERS, WHERE WE KNOW, WE THINK WE KNOW FROM STUDYING THE BRAIN AT THE END OF LIFE, THESE SYNDROMES ARE NOT RELATED TO MACROSCOPICALLY DISCOVERABLE AREAS OF BRAIN INJURY, PARTICULARLY MOOD DISORDERS, DEPRESSION, ANXIETY, AND SO ON. EVEN PSYCHOTIC.Nb DISORDER, SCHIZOPHRENIA ARE NOT ASSOCIATEDDED WITH RECOGNIZABLE FOCAL LESIONS THAT WE THINK ABOUT IN TERMS OF LOCALIZATION IN NEUROLOGY. INSTEAD, IT IS LIKELY THESE REPRESENT DEVELOPMENTAL DISORDERS THAT ARE VERY SUBTLE IN TERMS OF NEURONAL DENSITY AND CONNECTS, AND MORE ON REGULATION OF NEURONAL FUNCTION IN TERMS OF WHAT DRIVES SYMPTOMATIC EXPRESSION. THIS IN TURN MINES WE BENEFIT GREATLY THEN FROM NEUROIMAGING MOLECULAR APPROACHES THAT FOCUS ON THE RELEASE AN REGULATION OF NEUROTRANSMITTER FUNCTION AS OPPOSED TO STRUCTURAL ASPECTS OF THE BRAIN OR THOSE TARGETED NEURODEGENERATIVE PROTEIN DEPOSITIONS THAT I STARTED WITH. IN THIS REGARD THERE'S VERY EXCITING EVIDENCE WHICH IS EVOLVED OVER 10 TO 15 YEARS, AT THE DOPAMINE SYNAPSE, THIS IS A FEASIBLE APPROACH. SO RELATED TRACERS THAT TARGET THE DOPAMINE D-2 RECEPTOR HAVE BEEN FOUND TO BE SENSITIVE AND REPORT ON LEVELS OF ENDOGENOUS SYNAPTIC DOPAMINE AND HENCE RELEASE AND TURN OVER. THIS IS VERY INFORMATIVE IN MANY DISORDERS THAT WERE FELT RELATED TO DOPAMINE SIGNALING IN THE BRAIN. INCLUDING SCHIZOPHRENIA, AND IN TURRET SYNDROME IN A MOMENT. WE HAVE ANOTHER TRACER C-11 CARFENTONIL THAT CAN TELL US ABOUT SYNAPTIC LEVELS ENDOGENOUS SYNAPTIC LEVELS OF OPEN I DIDN'T DO PEPTIDES THE CARFENTINAL TARTS. THESE ARE TINY FRACTIONS OF NEURONAL POPULATION THE HUMAN BRAIN IS BUILT FROM. SO WHAT WE REALLY NEED SINCE THESE ARE VERY EXCITING TOOLS, I THINK AND GIVE US INSIGHT IN VIVO, INTO THE KIND OF REGULATION AND DISREGULATION THAT MAYBE DRIVING SYMPTOMATIC BEHAVIORAL KISS ORDERS, WE NEED SIMILAR APPROACHES TO MAJORITY OF NEUROTRANSMISSION IN THE BRAIN. SO GLUTAMATE NEURONS AND GABBA NEURONS 90% CELLS IN THE BODY IN OUR BRAINS NO SUCH TARGETING. ACETYLCHOLINE, NO SUCH TARGETING. SEROTONIN, WE THINK CRITICALLY DEPENDENT TO UNDERSTANDING AND TREATMENT OF EFFECTIVE DISORRERS SIMILARLY NO TRACER TARGET ALLOWS US TO INFER THIS. SO THIS IS WHAT WE NEED TO DEVELOP. LET ME SHOW YOU HERE IS A STUDY FROM DR. WONG'S LABORATORY JOHNS HOPKINS SHOWING AMPHETAMINE INDUCED RELEASE DOPAMINE IN STRIATUM OF PATIENTS WITH TURRET SYNDROME. IN THE TOP GREEN, THIS IS THE TIME ACTIVITY CURVE FOR C-11 RACLAPRIDE IN THE TURRET PATIENT. HERE IN THE RED CURVE IS THE SAME TIME ACTIVITY CURVE AFTER ADMINISTRATION OF AMPHETAMINE DOSE TO RELEASE DOPAMINE. YOU CAN SEE THE CURVE IS DISPLACED DOWNWARDS. THIS IS CONFER BECAUSE OF COMPETITIVE BECAUSE OF SYNAPTIC DOPAMINE. IN TURRET PATIENTS THAT POST AMPHETAMINE CURVE IS LOWER THAN IN NORMAL INDIVIDUALS, THIS IS TRUE WHEN YOU TRIPLE AND IT TURNS OUT ACTUALLY SPECIFIC TO THE VENTRAL STRIATUM, A VERY INTERESTING PART OF THE STRIATAL COMPLEX. WHAT WE NEED IS THIS KIND OF INFORMATION IN DEPRESSION. ARE THERE DIFFERENT FLAVORS THAT HAVE DIFFERENT MOLECULAR DISREGULATION THAT BENEFIT FROM DIFFERENT SPECIFIC INTERVENTIONS? WELL, WE ALL THINK SO BUT DON'T HAVE A WAY OF APPROACHENING A SCIENTIFICALLY STRONG AND SPECIFIC APPROACH. SO A SUMMARY OF WHAT I RAMBLED ON, WE NEED LIGANDS TA TARGET TAU AGGREGATE AND SELECTIVE AMONG DIFFERENT FORMS OF TAU, NEUROFIBRILLARY TANGLES VERY AMORPHOUS DEPOSITIONS. IT ONE NICE TO HAVE ALPHA SYNUCLEIN SPECIFIC MARKER THAT WOULD BE ABLE TO TELL US WHICH PATIENTS HAVE MULTIPLE SYSTEMS ATROPHY AN DON'T RESPOND TO TREATMENT FOR PARKINSON'S, VERSUS WHICH HAVE TAU OR OTHER DEPOSITIONS. IT WOULD BE NICE, IT WOULD BE IMPORTANT I THINK TO HAVE RIGOROUS BIOMARKERS THAT IMPROVE ALONE IN THE DEVELOPMENT OF NEW AGENTS. IT WOULD BE NICE TO HAVE UNDERSTOOD BIOMARKERS THAT INFORM US ABOUT DIFFERENT KINDS OF INFLAMMATION GOOD OR BAD. AND OTHER TIMES WE SHOULD AGGRESSIVELY INTERVENE VERSUS LET IT TAKE ITS COURSE. FOR MOST BEHAVIORAL NEUROLOGY AN NEUROSCIENCE ADDITIONAL BIOMARKERS OF SYNAPTIC TRANSMITTER LEVELS FUNCTION AND REGULATION ARE CRITICALCAL. THANK YOU. [APPLAUSE] >> THANK YOU VERY MUCH, DR. FREY. PLEASURE TO INTRODUCE YOUR NEXT SPEAKER, DR. JOSHUA FARBER FROM NIAID FROM NIH, IMMA'AMING CHEMOKINE RECEPTORS IN THE CASE OF CXCR4. WELCOME. THANK YOU. OKAY. GREAT. , WHETHER YOU WILL THANK THEM IS ANOTHER QUESTION. MY TALK IS GOING TO BE FAIRLY LIMITED COMPARED TO THE BROAD OVERVIEWS YOU HAVE HAD THUS FAR. I WAS HAPPY TO LEARN THAT NITDK, THEY DON'T KNOW MUCH ABOUT IMAGING SO WHEN I LEAVE NIAID THAT WILL BE MY NEXT INSTITUTE BECAUSE I'M NOT BY TRADE A TRADE IMMA'AMER, WHICH YOU WILL BE ABLE TO TELL FROM MY TALK. BUT I'LL TALK CHEMOKEEN RECEPTORS APPROXIMATE APPLICATION AS IMAGING TARGETS. SO TRAFFICKING IS ESSENTIAL IN TERMS OF DEVELOPMENT OF IMMUNE SYSTEM, HOMEOSTASIS OF IMMUNE SYSTEM AND HOW THE IMMUNE SYSTEM RESPONDS THE CHALLENGES. IT'S A HIGHLY MOBILE SYSTEM AND WITHOUT TRAFFICKING THE IMMUNE SYSTEM L CANNOT FUNCTION. SO THERE ARE A SERIES THAT REGULATE THE TRAFFICKING OF IMMUNE CELLS, AMONG THEM ARE CHEMOKINE AND CHEMOKINE RECEPTORS SO TO GIVE AN IDEA WHAT THIS FAMILY IS ABOUT, IT'S MORRIS THAN 40 SMALL SECRETED PROTEINS CHEMOTACTIC FOR LEUKOCYTES, SUBFAMILIES BASED ON SEQUENCES ABOUT SIGNAL THANK YOU 7 TRANSMEMBRANE DOMAIN G PROTEIN COUPLED RECEPTORS, 19 IDENTIFIED IN HUMANS SO RECEPTORS, COUPLED TO HETERO TRIAL RICK G PROTEINS, THE LARGEST RECEPTOR SUPER FAMILY IN THE GENOME, THAT IS THE SEVEN TRANS MEMBRANE RECEPTORS THAT MEDIATE A HOST OF BIOLOGICAL FUNCTIONS INCLUDING PARTICULARLY CHEMOTAXIS. THEY'RE THE CURRENT TARGETS OF MANY THERAPEUTIC AGENTS. ALL SMALL MOLECULE APPROXIMATE TAGNISTS OR AGONISTS. SO IN TERMS OF OVERVIEW OF THE VERY SIMPLE OVERVIEW BASIC PHYSIOLOGY WHAT CHEMOKINES TO, THIS IS ONE SUCH ILLUSTRATION, THIS IS AN INFLAMMATORY SITE OF BLOOD VESSEL, CARTOON FROM OLDER VIEW, A NEUTRAPHIL IN THE BLOOD VESSEL. IN ORDER FOR CELLS TO GET OUT INTO LYMPHOID ORGANS OR IN THIS CASE INFLAMMATORY SITE, THEY NEED TO ROLL ARREST ON THE SURFACE OF THE ENDOTHELIUM, THEY NEED TOADIED DOES ACROSS THE ENDOTHELIUM AND MIGRATE APPROPRIATE SITE WITHIN TISSUE. THE STEP THAT LEADS TO THEIR ARREST, DEPENDS ON THE SIGNAL THROUGH A CHEMOKINE RECEPTOR, ALSO DEPENDS ON SIGNALS DELIVERED THROUGH CHEMOTACTIC LIGANDS. I WANT TO SHOW YOU A LIST OF THE CXC CHEMOKINES BECAUSE WE'LL TALK ABOUT ONE RECEPTOR IN SOME DETAIL. SO THIS CXC CHEMOKINES ARE DIVIDED BASED ON SEQUENCE CONSIDERATIONS SO THOSE THAT TARGET NEUTRAPHILS AND MONOKNEW CLEAR CELLS. THE CHEMOKINES HAVE OLD NAMES A NEW SYSTEMATIC NOMENCLATURE, CHEMOKINES ARE CXCL AN CHEMOKINES IS CALLED CXCR KNOWED BY A NUMBER. SO THAT'S A LOT OF PROMISE SKEWTY IN THE SYSTEM, COMBINED TO MORE THAN ONE RECEPTOR AND ONE RECEPTOR SUCH ADS CXCR4 COMBINED TO MULTIPLE CHEMOKINES. WE'RE GOING TALK MOST OF THE TALK ABOUT CXCR-4 A RECEPTOR WITH SINGLE LIGAND, CXCL-12 AND THOUGH LOW EXPRESSION ON NEUTRAPHILS, IT TARGET T MONTH NUCLEAR CELLS SUCH AS T AND B CELLS AND MONOCYTES. CHEMOKINE SYSTEM IS IMPORTANT IN MANY ASPECTS AS I -- MANY ASPECTS OF THE FUNCTION OF THE IMMUNE SYSTEM AND CXCR-4 PARTICIPATES IN A NUMBER OF THESE CATEGORIES INCLUDING THE DEVELOPMENT OF THE IMMUNE SYSTEM IN TERMS OF ORGANIZING THE ANATOMY AND IMMUNE RESPONSE, CXCR-4 IS EXPLOITED BY PATHOGENS I'LL MENTION THE PASSING AND CXCR-4 IS ONE OF TWO TARGETS CURRENTLY FDA APPROVED DRUG. TO SHOW YOU WHAT IT LOOKS LIKE CXCR-4 WAS THE FIRST CHEMOKINE RECEPTOR AND HANDFUL OF TRANSMEMBRANE RECEPTORS CRYSTALIZED IN STRUCTURE TO DETERMINE IT HAS EXTRA CELLULAR END TERMINUS, ENDOCELLULAR C TERMINUS 7 TRANSMEMBRANE ALPHA HELICES, THREE EXTRA CELLULAR LOOPS AND NOT SHOWN HERE INTRACELLULAR LOOPS. WHAT ABOUT THE BIOLOGY, IT'S EXPRED THE IN DIVERSE RING OF CELLS. INCLUDING MONONUCLEAR CELLS AND MARROW PROGENITOR CELLS BUT ALSO EXPRESSED OUTSIDE OF LEUKOSITES ON ENDOTHELIAL CELLS AND CERTAIN EPITHELIAL CELLS. IT'S A CO-RECEPTOR FOR STRAINS OF HIV, THIS IS A LOT OF INTEREST IN RECEPTOR, INITIALLY BECAUSE OF THIS. AND IT'S THERAPEUTIC INTEREST. THE CXCR4 LIGAND IS CXCR-12 EXPRESSED CONSTITUTIVELY IN NUMBER OF CELLS LYMPHOID WAR ORGANS AND LIVER AND LUNG. IN ADDITION TO ROLE IN LEUKOCYTE TRAFFICKING SPECIFICALLY, CXCR4 PLAY PLAYS A FUNDAMENTAL ROLE IN MIGRATION OF PROGENITOR CELLS DURING EMBRYONIC DEVELOPMENT OF HEMATOPOIETIC AND CENTRAL NERVOUS SYSTEM. ITS ROLE IS ILLUSTRATED IN PART OF BY THESE EARLY DATA ON THE CXCR-4 KNOCKOUT MICE. THIS IS FLOW CYTOMETRY LOOKING AT BONE MARROW IN THE FETAL MOUSE, MAYBE YOU CAN'T SEE THIS TOO WELL BUT THESE ARE WILD TYPE BONE MARROW CXCR-4 KNOCK OUT BONE MARROW, THESE MARKERS IDENTIFY NEUTRAPHIL AN MONOCYTE PRE-CURSORS ABSENT IN BONE MARROW FOR KNOCK OUT ANIMALS AS WELL AS KARYOCYTES WITH WHICH ARE ALSO ABOUT SEN IN IF THE CXC ALREADY-4 IF YOU LOOK IN VITRO THIS THIS IS THE POSH PART OF HEMATOPOIETIC STEM CELLS, PROGENITOR CELLS RETAINED WITHIN THE BENEFIT MARROW AND PROPER DEVELOPMENTAL NICHE FOR THEIR DEVELOPMENT. THIS BIOLOGICAL ACTIVITY REALLY IS THE BASIS OF THE DRUG APPROVED AS ANTAGONIST FOR CXCR4 WHICH I'LL TALK ABOUT IN A MINUTE, CALLED AMD 3100, IT'S NOW (INDISCERNIBLE) TRADE NAME IS MOSENBIL, SOME SLIDES MAY GO BACK AND FORTH BEFORE USINGING A SHORTHAND JUST CALLING IT AMD OR LUREIXAFO ARER, IT WAS DEVELOPED AS AN ANTI-HIV DRUG BUT IT REALLY FAILEDDED IN THOSE EARLY CLINICAL TRIALS FOR REASONS WE WON'T GO INTO PROBABLY. HOWEVER, BECAUSE OF ITS ROLE ON HEMATOPOIETIC STEM CELLS THIS ANING THENIST LIBERATES FROM THE BONE MARROW TO PERIPHERAL CIRCULATION. AND THIS USEFUL IN HARVESTING STEM CELLS HARVESTING TRANSPLANTATION AS PART OF CANCER CHEMOTHERAPY. DRUG WAS APPROVED IN 2008 AS A MOBILIZING AGENT IN COMBINATION IN PATIENTS WITH NONHODGKIN'S LYMPHOMA OR MULTIPLE MYELOMA. IT IS WELL TOLERATED THOSE THIS INDICATION GIVEN FOR SEVERAL DAYS IN A ROW SO SO FAR IT'S NOT VALIDATED IN ANY PROTOCOLS FOR LONG TERM THERAPY. SO NOT TO READ THIS OBVIOUSLY BUT SHOW YOU THIS IS ONE OF MANY CXCR4 INHIBITOR THAT ARE BEING EVALUATED FOR CLINICAL INDICATION THOUGH THE ONLY ONE CURRENTLY FDA APPROVED. I WANT TO POINT OUT INDICATIONS ARE INHIBITORS BEING DEVELOPED FOR THE TREATMENT OF CANCER SUCH AS MULTIPLE MYELOMA AND NON-HEMATOLOGIC MALIGNANCIES. THERE'S A STORY ABOUT CXCR4 IN CANCER AND THERE'S A LARGE LITERATURE ON CXCR4 IN CANCER BECAUSE CXCR4 IS EXPRESSED BY MORE THAN 23 TYPES OF HUMAN CANCERS, THERE ARE SEVERAL MECHANISMS TO SUGGEST THAT IT UP REGULATES CXCR4 IN CANCER INCLUDING HIF-1 ALPHA, TRANSCRIPTION FACTOR SENSITIVE HYPOXIC CONDITIONS. CXCR4 AND LIGAND ARE REPORTED TO PLAY MULTIPLE ROLES IN TUMORS INCLUDING ENHANCING SURVIVAL AND INCREASING INVASIVENESS, METASTASIS ANGIOGENESIS AND STROMEAL ELEMENTS. OBVIOUSLY BASED ON MOUSE MODELS. HIGH LEVELS OF CXCR4 EXPRESSION IN HUMAN STUDIES OF ASSOCIATED CXCR4 EXPRESSION WITH OUTCOME ARE ASSOCIATED WITH POOR PROGRESS ANYSIS AND RESISTANCE TO CHEMOTHERAPY. I WANT TO DIGRESS FOR A HE COULD SECOND TO MAKE A POINT ABOUT HUMAN STUDIES. UP IN OF YOU PROBABLY WORK IN THIS AREA, BUT MANY -- THESE STUDIES ARE ACTUALLY THE MOUSE STUDY MS. ARE QUITE CONVINCING ON ROLE FOR C CXCR4 IN CANCER PARTICULARLY METASTASIS OF CERTAIN SITES SUCH AS BONE. THE HUMAN CORRELATION STUDIES REALLY I CANNOT BE ACCEPTED WITHOUT A GRAIN OF SALT TO SOME EXTENT. SO THIS IS JUST AN EXAMPLE OF ONE OF THESE STUDIES AND I DON'T KNOW IF IF YOU CAN READ THIS, BUT POINT IS THIS IS STUDY ON BREAST CANCER AND ANALYSIS WAS DONE LOOKING AT THE IMPORTANCE OF NUCLEAR EXPRESSION OF RECEPTOR AND WHICH SAMPLES AND WHICH PATIENTS SHOWED NUCLEAR EXPRESSION VERSUS CYTOPLASMIC EXPRESSION SO MANY STUDIES IN LITERATURE WHICH USE MORE THAN HUMAN STUDIES OF HUMAN TISSUE USE MORE THAN A DOZEN DIFFERENT THE ANTIBODIES AGAINST CXCR4 THAT MOSTLY ARE L RELATIVELY POORLY CHARACTERIZED FOR USE IN KIND OF TISSUES THEY'RE USED TO STAIN FOR. AND FOR EXAMPLE, NUCLEAR EXPRESSION OF RECEPTOR MAKES NO BIOLOGICAL SENSE, THERE'S NO ROLE FOR THIS RECEPTOR IN NUCLEUS, AS FAR AS I KNOW, WE HAVE TO KEEP AN OPEN MIND BUT I WILL BE SKEPTICAL OF STUDIES AS MANY DO THAT SHOW NUCLEAR EXPRESSION. SO RECENTLY ANOTHER RAD BY MONOCLONAL ANN BODY IS DEVELOPED THAT WORKS WELL IN FIXED TISSUES THE PATHOLOGISTS IN THE CANCER INSTITUTES HAVE DEVELOPED A GOOD PROTOCOL FOR USING THIS ANTIBODY TO SHOW YOU THIS IS EXPRESSION OF CXCR4 AND WE HAVE BEEN RE-EVALUATING THE EXPRESSION OF CXCR4 IN VARIOUS CANCERS. AND THIS IS EXPRESSION OF SMALL CELL CANCER ON DIFFERENTIATED LUNG CANCER, SQUAMOUS CELL CARCINOMA, THERE'S NO NUCLEAR STAINING JUST MEMBRANE STAINING WHERE THE RECEPTOR IS EXPRESSED. I'LL SKIP THE NEXT SLIDE WHICH IS A SUMMARY OF SOME OF OUR DATA ON LUNG CANCER. SO HOW MIGHT CXCR4 BE USED IN CANCER THERAPY? WHAT MIGHT ITS USE BE? IT MIGHT BE USED TO DETECT METASTATIC LESIONS IN CERTAIN SPECIFIC CIRCUMSTANCES BUT PRINCIPALLY COULD BE USED AS A BIOMARK FORE PROGNOSTICATION OR PREDICTING RESPONSE TO THERAPY, IT COULD BE BLOCKING CXCR4 IS AGAIN BASED ON MOUSE DATA MAYBE USEFUL AS SEN ADVERTISER FOR OTHER THERAPIES OR AGAIN BASED ON MOUSE DATA IT'S POSSIBLE BLOCKING CXCR4 HAS -- WOULD HAVE AN ANTITUMOR EFFECT INHIBITING TUMOR GROWTH AND METASTASIS. SO IT WOULD THEREFORE BE USEFUL AND IMPORTANT TO KNOW WHERE CXCR4 IS EXPRESSED TO ENABLE APPLICATIONS WE WOULD BE INTERESTED TO IDENTIFY EXPRESSION IN VIVO IN A WAY THAT'S NON-INVASIVE, ALL LEAGUE IT IS WHOLE TUMOR ENTIRE TUMOR THAT'S REASONABLY QUANTITATIVE AND OF COURSE IS REPEATABLE. SO WE HAVE BEEN FOCUSED ON USING THE DRUG TO INVESTIGATE THIS OPPORTUNITY. SO ORI JACOBSON, POST DOC FELLOW WITH DR. NIBIB HAD THE INSIGHT THAT THE ABILITY OF PLUREXIFOR TO KEY LATE METAL COULD BE USED TO DEVELOP A -- IN THIS CASE LOAD WITH COPPER 64. I GUESS Y'ALL KNOW MORE ABOUT THAT THAN I DO BUT TO REMEAN YOU IT'S NOT A GREAT ISOTOPE BECAUSE IT HAS FOR PET SCANNING BECAUSE IT ONLY HAS 18% POSITRON DECAY. AND HAS A LONG HALF LAFE FOR MOST AGENTS YOU DEAL WITH AT 12 HOURS AND IT IS BEING USED INVESTIGATIONALLY AS COPPER ATSM ADMINISTERD AT A DOSE OF 25 MILLION CURES. SO -- MILICURES. SO THIS IS TO DEMONSTRATE IF YOU LOAD AMD 3100 WITH WITH COPPER AND INHIBIT MIGRATION OF CELLS MEDIATED THROW CXCR4, IT FUNCTIONS JUMP AS WELL AS THE UNLOADED MOLECULE. IT'S PUBLISHED THAT METAL KEYLATED AMD 3100 IS MORE AFFECTIVE BINDING TO RECEPTOR THAN UNMODIFIED DRUG. IF YOU LOOK AT BIODISTRIBUTION IN VIVO DUB BY INJECTIONING THE AGENT CUTTING OUT ORGAN TISSUES AN ORGANS AN COUNTING THEM YOU SEE THAT T IT IS A TIME COURSE, THE DRUG ACCUMULATES IN LYMPHOID ORGANS SUCH AS SPLEEN, BOB MARROW, LYMPH NODES, YOU MIGHT SAY UNFORTUNATELY ACCUMULATES HIGH LEVELS IN KIDNEY, LIVER AS WELL AS KIDNEY. THE ACCUMULATION IS BLOCKED BY USING COLD COPPER AMD WHICH IS WHAT THIS DEMONSTRATES SHOWING THE BINDING IS USING TUMORS EITHER EXPRESS ORGANIZE NOT EXPRESSING CXCR4, THIS IS WHAT I WOULD CALL A POOR MAN CT, HERE ARE THE TWO SUBCUTANEOUS TUMORS THIS ONE NOT PRESSING, THIS ONE EXPRESSING. YOU CAN SEE THAT THE PET IMAGE OF EXPRESSING TUMORMENT IN THIS CASE IF WE TOOK IT OUT BY FLOW CYTOMETRY, EXPRESSION OF RECEPTOR IT REMAINS EXTREMELY HIGH SIMILAR TO WHAT IT WAS WHEN TUMOR WAS IMPLANTED. THIS IS THE BIODISTRIBUTION BY CUTTING OUT AND COUNTING THE IT SHALL SHOE, THIS IS A RELATIVELY HIGH ACCUMULATION IN THE CXCR4 EXPRESSING TUMOR BUT IN THE IN THE NON-EXPRESSING TUMOR, THIS CAN BE BLOCKED APPROPRIATELY BY USING THE COPPER -- COLD COPPER DRUG LABELED WITH COLD COPPER OR THE DRUG ITSELF WITHOUT COPPER AT ALL. ANOTHER CASE OF SUBKYE TAPEIOUS TUMOR, I SHOW YOU THIS TO POINT OUT IN THIS PARTICULAR CASE WE SEE IMAGENING THE TUMOR, CXCR4 EXPRESSING TUMOR WITH WITH CXCR4 AT THIS LEVEL BEFORE IMPLANTATION LOST A GREAT DEAL OF EXPRESSION DURING THE TIME IN VIVO AND NUMBER WE'RE ABLE TO IMAGE TUMOR AND FINALLY IN A MODEL WHERE WE INJECT TUMOR INTRAVENOUSLY TO PRODUCE METASTATIC DISEASE IN THE LUNG EITHER WITH A LOUIS LUNG CAR KNOW MA LINE OR CHINESE HAMSTER CELL INJECTED INTRAVENOUSLY YOU CAN VISUALIZE TUMORS IN THE LUNG. HERE, HERE AND HERE AND YOU CAN SEE ACCUMULATION BROCKED AND YOU CAN SEE THE IMAGE AFTER BLOCKING YOU LOSE THE ABILITY -- THE IMAGE> NOW, WE'RE NOT THE ONLY ONES WHO USED THIS AGENT. I'M SORRY. JUST BEFORE GOT TO THAT, TO SHOW WE HAD REASONABLY HIGH RATIOS. AGAIN THESE HIGH HI ARTIFICIAL MODELS OF THE CXCR4 EXPRESSING TUMOR TO THE BLOOD AND MUSCLE AND THE POSITIVE VERSUS THE NEGATIVE TUMOR IN TERMS OF UPTAKE. JUST TO SAY WE'RE NOT THE ONLY ONE, AGAIN USING -- WHO USED THIS SO THIS IS A FIGURE FROM A PAPER FROM DR. PROBLEM FOR'S LABORATORY IN ORTHO TOPIC BREAST CANCER MODEL TO CELL LINES TO BREAST -- HUMAN BREAST CANCER CELL LINES ONE EXPRESSING CXCR4, ONE NOT. THE PET T CT AND THE FUSED IMAGE S. SO THIS AGENT IS NOT THE ONLY ONE BEING DEVELOPED FOR THE PURPOSE OF IMAGING CXCR4, THIS IS A GREAT DEAL OF INTEREST IMAGING THIS TARGET. THERE ARE A NUMBER OF POTENTIAL PROBES HAVE BEEN AND BEING DEVELOPED SO THESE ARE MOVE -- I HAVE A SELECT GROUP. THESE ARE SOME OF THE SINGLE PHOTON PROBES INCLUDING PEPTIDE ANTAGONIST AND ANTIBODY AGAINST CXCR4 AND THE LIGAND ITSELF, CXCR4 OR STF-1, ALSO LABELED WITH (INAUDIBLE). IN TERMS OF PET, THIS IS FAR FROM -- THIS IS ONLY A SMALL NUMBER OF THOSE WHO HAVE AMD 3100 I SHOWED YOU ANOTHER RELATED MOLECULE, ANOTHER PEPTIDE OF CXCR4. ALL THESE HAVE OBVIOUS ADVANTAGES AN AT THIS ADVANTAGES, LIMITATIONS FOR AMD 3100, THE LIMITATIONS ARE HIGH ACCUMULATION IN THE LIVER AND CERTAIN OTHER NORMAL ORGANS THIS SOME CASES COULD BE A DISADVANTAGE IN IMAGING CANCER. IT'S BIG ADVANTAGE IS NOW THERE ARE POTENT THIAL OTHER APPLICATIONS WHICH I AM PARTICULARLY INTERESTED IN FOR THIS AGENT BEYOND CANCER BECAUSE I'M NOT AN ONCOLOGIST USE THIS BECAUSE OF ITS EXPRESSION OF MONONUCLEAR CELLS, FOR IMAGING CHRONIC INFRAMATION IN TISSUE. IF AGGREGATION OF LYMPHOID CELLS OR MONOCYTES, ALSO BECAUSE IT IS GOOD IMAMMING BONE MARROW, HAS POTENTIAL IMAGING BONE MARROW UNDER CERTAIN SITUATIONS THAT WOULD BE DESIRABLE SUCH AS IN RECONSTITUTION AFTER HEMATOPOIETIC STEM CELL TRANSPLANTATION. CXCR4 AS I SHOWED YOU IS ONE OF A FAMILY OF CHEMOKINE RECEPTORS, YOU CAN SPECULATE OTHER RECEPTORS MIGHT BE TARGETS THAT COULD BE USED FOR IMAGING AND OF COURSE YOU CAN'T SEE THIS, BUT THIS IS A TABLE FROM 2010 ABOUT A WHOLE VARIETY OF SMALL MOLECULE AGENTS THAT ARE BEING DEVELOPED AT SOME STAGE OF CLINICAL DEVELOPMENT TO TARGET A VARIETY OF CHEMOCHAIN RECEPTORS FOR A NUMBER OF INDICATIONS. SO THERE MANY SMALL MOLECULES DEVELOPED BY THE FARM SUECAL INDUSTRY TO TARGET THESE MOLECULES. IN SOME CASES TO TREAT INFLAMMATORY DISEASE THOUGH I WOULD SAY THAT PROMISSION IS YET TO BE REALIZED. SOME CASES TO TREAT HIV, AND SOME CASES CXCR4 TO TREAT STEM CELL TRANSPLANTATION OR CANCER THERAPY. ONE CAN MARGE USING THESE AGENTS, DRIVE ADVERTISETIZING FOR THE PURPOSE OF IMAGING AND ONE POTENTIAL APPLICATION IS TO IDENTIFY SPECIFIC LEUKOCYTE SUBSETS BEYOND LOOKING AT INFLAMMATION IN GENERAL, TO BE ABLE TO USE RECEPTORS AT LEAST THE -- THOSE RECEPTORS THAT HAVE AN INTERESTING AND SOMEWHAT SPECIFIC EXPRESSION PATTERN AS TARGETS FOR IMAGING, CXCR4 AND 2 WHICH ARE NOT ABSOLUTELY SPECIFIC FOR NEUTRAPHILS ARE EXPRESSED BY FAR, VERY MUCH HIGHER LEVELS OVERNEW NEUTRAPHILS AN UNIFORMLY AS COMPARED TO OTHER CELLS. TO CONCLUDE, CXCR4 MAYBE A TARGET OF INTEREST FOR IMAGING CANCER AND OTHER CLINICAL CONTEXT, COPPER 64 (INDISCERNIBLE) POTENTIAL AGENERAL FOR IMAMMING CXCR4 BY POE WITH LIKELY LIMITATIONS AND AGAIN, PERHAPS SOME OF THESE OTHER AGENTS THAT ARE BEING DEVELOPED WILL BE SUPERIOR AND ULTIMATELY MORE ADVANCETYIOUS. CHEMOKINE RECEPTORS MIGHT SERVE AS TARGETS IMAMMING SPECIFIC LEUKOCYTE SUBSETS AN INGRAMTORY SO I NEED TO THANK SOME PEOPLE WHO CONTRIBUTED TO THIS BECAUSE MY LAB WORKS ON CHEMOKINE RECEPTORS AND BUT I DEPEND ON IN PEOPLE TO ASSIST WITH THIS PROJECT, THE PROJECT WAS BORN THROUGH THE WORK OF ORI JACOB SEN WORKING WITH DALE SITTER IN SEAN KING'S LAB IN NIBIB. SHE WAS COLLABORATING WITH HER HUSBAND WHO WAS A POST-DOCTORAL FELLOW IN MY LAB AN THIS PROJECT WAS WAS BORN FROM THEIR INSIGHTS AND THEIR LABORS. WE HAVE HAD AGAIN A NUMBER OF COLLABORATORS IN THE PETER CHOIKI THE MOLECULAR IMAGING PROGRAM NCI IS AN ABSOLUTELY CRITICAL PERSON IN ALL ASPECTS OF THIS PROJECT. STEPHANIE PEDALUGA FROM NCI WHO PERFECTD THE WAY OF STAINING FOR CXCR4 IN TUMOR SAMPLES. AND WE HAVE HAD A GREAT DEAL OF HELP FROM THOSE WHO SYNTHESIZE THE DRUG, THOSE WHO HELPED ANALYZE ITS BIODISTRIBUTION, PAULA JACOBS WHO IS GIVEN US ADVICE RESEASONLY FROM PETER HERSCOVITS AND (INDISCERNIBLE) MOLECULAR ONCOLOGY BRANCH OF THE NCI. SO I DON'T SEE ANYBODY STANDING UP. IT MEANS I MUST HAVE BEEN ON TIME. MAYBE EVEN EARLY SO THAT MEANS I GUESS I CAN HAVE A QUESTION, MAYBE NOT. ARE YOU STANDING UP BECAUSE YOU FORGOT THAT I WAS HERE? [LAUGHTER] >> YOU WERE ENGROSSED IN TALK. WHAT AN OUTSTANDING ANSWER. THANK YOU SO MUCH. >> ANY QUESTIONS? ALL RIGHT. THANKS VERY MUCH. [APPLAUSE] >> WE'LL TAKE A BREAK AND RESUME AT 10:15. THERE'S A CAFETERIA ON THE LOWER LEVEL. MY NAME IS RICHARD CONRAD, DIRECTOR OF DIVISION APIPELINED SCIENCES AN NIBIB. FIRST WE FOCUSED ON UNMET CLINICAL NEEDS AN SECOND WE'LL LOOK AT SOME OF THE MODALITIES SPECIFIC AREAS AND MULTI-MODAL ASPECTS SO TO MOVE ON AS QUICKLY AS WE CAN. THE FIRST SPEAKER WILL BE THOMAS MEADE NORTHWESTERN P UNIVERSITY. SPEAKING ABOUT MR PROBES. >> THANK YOU. IT'S ALWAYS A PLEASURE TO COME BACK TO THE NIH SINCE YOU NEED MORE ID THAN GOD TO THE GET IN HERE. I REMEMBER A TIME I COULD WALK FROM THE RAD SOP ACROSS THE GRASS TO THE ADTOR YUM AND NEVER GET LOOKED AT. THOSE WERE THE GOOD OLD DAYS. I'M GOING TO FOCUS ON MR PROBES, THAT'S HARD TO DO CONSIDERING THERE ARE NUMBER OF LABORATORIES ON THE PLANET WORKING ON THESE, ESPECIALLY THE LAST 15 YEARS. WHY MRI? I DON'T HAVE TO TELL THIS CROWD WHY. IT'S NON-INVASIVE, EXCELLENT SPATIAL AND TEMPORAL RESOLUTION. IF YOU CAN GET THE LIGHTS DOWN I CANNOT BE BLINDED. THIS IS WITH A COLLEAGUE OF MIC MIKE MERKAL NORTHWESTERN AFTER SOMETHING IN A PATHOLOGICAL WAY, THAT HAPPENS TO BE THAT ANEURYSM. NOISING THE THAT NOT JUST THE PROBES THAT ARE MAKING A HUGE DIFFERENCE, IT'S THE TECHNOLOGY OF COURSE AND THE PULSE SEQUENCES. THESE FLOWS AND COLORS THAT YOU SEE INDICATE THE PARENTAL FLOW AND INDICATE TYPES OF PATHOLOGY. SO WHY METALS AND MEDICINE? THEY HAVE AN ACCESS THAT CARBON AND SOME OF THE ELEMENTS DON'T HAVE, COORDINATION GEOMETRIES WE CAN DEAL WITH. I WON'T SPEND A LOT OF TIME ON THIS BUT THERE ARE LIGANDS WITH THIS AS WELL. AS WE LOOK TO FUNCTION WE WANT TO BE ABLE TO TURN THINGS ON AND OFF AT WILL. ONE WAY TO DO THAT IS TO HAVE TUNEABLE LIGAND EXCHANGE. I'LL MENTION SOMETHING ABOUT THAT COMING UP. THE MAGNETIC PROPERTIES OF COURSE IS SOMETHING I SPEND MOST TIME ON. THE LEFT IS AN IRON NANOPARTICLE, OBJECT RIGHT IS GADOLINIUM KEY LATES. RADIO ACTIVITY OF COURSE YOU WILL HEAR ABOUT THAT FROM MARTY AND OTHERS AND WE DON'T -- WE CAN REACH INTO A BAG THAT'S DEEPER THAN JUST CARBON HYDROGEN SULFUR AN NITROGEN. THESE ELEMENTS MAKE PACK AND CT POSSIBLE. I WANT TO SAY BRIEFLY WHAT IT IS THAT MR CONTRAST AGENTS AND CHALLENGES FACE. THAT IS PRIMARILY ONE OF SENSITIVITY. WHAT YOU MAY NOT REALIZE, SURE THIS CROWD DOES, WHEN YOU LOOK AT MR IMAGE IN A CONTRAST AGENT YOU'RE NOT LOOKING AT THAT TIME AGENT, YOU'RE LOOKING AT THE EFFECT OF THE AGENT ON LOCAL WATER. SO ITS SENSITIVITY IS A BIG PROBLEM. WITH RADIO ACTIVITY YOU CAN SEE ALMOST ATOMS AND OPTIMAL MICROSCOPY, THE REAL PROBLEM IS INDEED ITS DETECTABILITY. SEW PLAY WITH THREE PARAMETERS TO MAKE THEM BROUGHTER. THESE ARE THE THREE NUMBER OF WATER MOLECULES. ROTATIONAL CORRELATION TIME AND LENGTH OF TIME WATER SPENDS ON THAT GADOLINIUM, ALL THREE PARAMETERS ARE ESSENTIAL TO CONTROL TO MAKE THEM BRIGHTER. SO IF WE WANT TO INCREASE RELACKSIVETY WE HAVE -- THESE ARE THE ALMOST FDA APROVED KNOCKED OUT RECENTLY, GAVE GADOLINIUM A BAD NAME WHEN I'S PROPERLY KEYLATED IT'S NOT TOXIC UNBEKNOWNST TO RADIO LOGICAL COMMUNE THE AND FDA. IF YOU USE KEY LATE HERE, THESE ARE OPEN KEY LATES MEANING THEY DON'T FORM MACRO CYCLES, THE FORMATION CONSTANTS ARE BETWEEN 4 AND 6 ORDERS OFFING MAGNITUDE LESS THAN THIS MOLECULE HERE, WHILE THESE ARE VULNERABILITIES, THIS IS THE 10 TO THE 25th AND IS NOT A PROBLEM. GAD GOT A BLACK EYE WITH NSF TOXICITY BUT THAT WAS BECAUSE OF THIS MOLECULE HERE AND IF YOU KNOW YOUR BASIC CHEMISTRY AND PROTONS ARE LOW, IF YOU GET TO LOW PH KNOCK THOSE OUT SO THIS IS KNOCKED OUT. THESE ARE THE REST. ONE NUMBER TO TAKE AWAY IS THE CURRENT FDA APPROVED AGENTS HAVE RELACKSIVETY, DIRECTLY RELATED TO BRIGHTNESS, THAT'S FOUR MILLIMOLAR PER SECOND. THIS IS A GAME OF NUMBERS. THE BIOMARKERS OF INTEREST TO LOOK AT IN VIVO ANYWHERE FROM MICRO TO 10 TO THE 12, PET SENSITIVITY SITS IN THERE, GREAT IN TERM OF MAKING PROBES THAT DETECT THOSE TYPES OF BIOMARKERS. GADOLINIUM AND SENSITIVITY IS WAY BEHIND, TEN TO THIRD MINUS TEN TO THE FIFTH. SO YOU HAVE TO GO BACK TO THAT EQUATION. I WANT TO LOOK AT TWO CLASSES OF TYPES OF AGENTS PARASYCESSED HYPERPOLARIZED TECHNIQUES BUT I WILL SAY WHAT WE DO IN OUR LAB REPRESENTATIVE MANY OTHER LABS, WE'RE NOT THE ONLY ONE WORKING ON THESE BUT TARGETED AGENTS, NON-TARGETED, SUPER MOLECULAR NANOAPPROACHES AND (INDISCERNIBLE) SO REMEMBER THAT NUMBER. I WANT TO KEEP THAT IN MIND WHAT IS THE CHALLENGES, SIGNAL AMPLIFICATION. RELACKSIVETY FOUR MILLIMOLAR A SECOND MEANS YOU'RE INJECTING MILLIMOLAR QUANTITIES OF AGENT IN. THAT'S SIMPLY UNACCEPTABLE. IT MAY WORK IN CLINIC TODAY FOR SOME OF THESE VASCULAR STUDIES BUT IT SIMPLY ISN'T BRIGHT ENOUGH TO MAKE A DIFFERENCE SO APPROACHES IN OUR LAB ARE THREE. WE MAKE AMPLIFICATION, MULTI-MERIT, WHAT DOES THAT MEAN? MORE THAN ONE GADOLINIUM, WE INCREASE THE LOCAL GADOLINIUM CONCENTRATION, IMPROVE THE RELACKSIVETY. THAT'S ONE APPROACH. THE SECOND IS TO USE THE NANOPARTICLES IDEAL FOR PUTTING THINGS AN CARGO ON ONE PRODUCT, ONE PARTICLE. I WILL SAY IRON OXIDE PARTICLES HAVE TAKEN A BLACK EYE PROBABLY GOOD REASON SO WE MOVED AWAY FROM IRON, SPEND MOST TIME ON GOLD AND COPPER AND IN THIS CASE, THIS IS MULTIPLY LABELED SPECIES I COLLABORATE WITH CHAD MERCK AT NORTHWESTERN AND I'LL MENTION SPECIFICS ABOUT THAT. FINALLY ACTIVATION, YOU'LL GET FUNCTIONAL DOMAINS LIKE WHAT OPTIMAL MICROSCOPY AND 2 FDG BROUGHT TO OTHER MODALITIES WITH CAN WE DO THIS AND WE PIONEERED THIS 15 YEARS AGO MAKING AGENTS TURNING ON AND OFF. WHEN YOU TURN IT ON AND OFF SELECTIVELY THAT GIVES YOU A BOOST IN SENSITIVITY THAT WE COULDN'T HAVE GOTTEN OTHERWISE. SO MULTI-FUNCTIONAL, THESE ARE SERIES OF MOLECULES, BRICK IN TERMS OF TOXICITY AND IN TERMS OF BRIGHTNESS WE STARTED WITH 4 MILLIMOLAR PER SECOND, THE REAL PROPERTIES THAT WE LIKE ABOUT THEM, THEY'RE SIMPLE TO DESIGN, WE CAN HAVE UNDERGRADUATES MAKE THEM IN TWO WEEKS OF ENTRYNY IN THE LAB. EASILY CHARACTERIZED HIGHLY STABLE AND VERY NON-TOXIC. WE GET OUT OF THAT RELACKSIVETY A JUMP ON THE MULTI-MERIC SYSTEM TO 85. THE OVERALL RELACKSIVETY IS 85 PER GAD IS 17 INSTEAD OF FOUR. YOU CAN START INJECTING AND DETECT THING CONCENTRATIONS THAT ARE NOW IN THE MICROMOLAR REGIME INSTEAD OF MILLIMOLAR. YOU CAN INJECT INSTEAD OF MILLIMOLAR QUANTITIES, MICROMOLAR. ANOTHER WAY TO DO THAT, MAREN AND I I WERE TALKING ABOUT THIS EARLIER, TO MAKE THE MULTI-MERIC STRUCTURES VERY RIGID AND BRIGHT SO THE TOTAL IS -- YOU CAN PUT ABOUT ANYTHING YOU WANT ON IT. SO ONE OF THE MOLECULES THAT I THINK WE -- I WON'T HAVE TIME THE TALK ABOUT IS SIDE CHAINS YOU CAN TAKE THOSE CELLS EXVIVO AND WE'VE PUT THEM IN VIVO AN THESE AGENTS STICK TO THE CELLS FOR ALMOST A YEAR OR WE'RE UP JUST OVER A YEAR WITH BOTH STEM CELLS AN BETA ISLETS SO THIS IS A WAY TO INCREASE RELACKSIVETY AND NOT INTERFERE WITH THE TOXICITY. YOU DON'T HAVE TO GET INTERCELLULAR, IT JUST LOCKS IT IN. WHEN I THINK OF SUPER MOLECULAR APPROACHES, WE HAVE BEEN TAKING PEPTIDE AMPLY FILES WHICH HAVE PROPERTIES THAT YOU CAN DIAL IN IN TERMS OF PEPTIDE RECOGNITION PROPERTIES AND SOME OF ITS MATRIGEL, WE DECORATE THESE IN THE SAME WAY I MENTIONED WITH GADOLINIUM UNITS, THESE ARE FIBERS THEY MAKE AND ULTIMATELY WHAT YOU CAN DO WITH THOSE IS PUT THEM IN FIBER GELS, THEY CAN BECOME GELS, LOAD WITH DRUGS, YOU CAN LOAD WITH ALL SORTS OF OTHER CARGO THAT YOU WOULD LIKE, THIS GEL IS GLOWING SO THERE IS NO CONTRAST AGENT, YOU CAN SEE BACKGROUND FROM THAT, AS YOU INCREASE THE GADOLINIUM FIBERS WE MAKE IN THESE. NOW YOU HAVE A GEL DETECTABLE FOR LONG TERM STUDY SO IN VIVO LOOKING AT HEART. THIS IS WHERE THE GEL INSERTED IN THIS IS POSTOP, LOOK AT THE BRIGHTER READING HERE AND HERE. THIS IS THREE WEEKS POST OBJECTION, YOU CAN DETECT FOR LONG PERIODS OF TIME SO YOU CAN FATE MAP YOUR GEL WHERE WILL CARRYING DRUGS OR NOT SO OVER TIME THIS DISSIPATES AND ABSORBED YOU CAN TRACK AND TAG IT. SO THAT'S IN VIVO, WE'RE E HAPPY WITH THAT WITH GOOD RELACKSIVETY OF 40 PER. SO LET'S MOVE TO TARGETED AGENTS, ONLY GOING SHOW ONE EXAMPLE, THIS IS WITH HAS BEEN WEIGH WITH JOANNENA BURR DEBT, WHERE WE'LL TAKE A SIMPLE APPROACH TO THIS, IN FACT IT WAS INVERTD TO APPROACH WE USED WITH TRYING THE MAKE THINGS WRIGHT BRIGHT. WE'RE TAKING A GADOLINIUM COMPLEX AND PUT A PROGESTERONE MODEL ON IT WITH DIFFERENT LINKERS TRYING TO OPTIMIZE THESE. HERE IS ONE TIME YOU DON'T WANT THE AGENT BRIGHT. REASON FOR THAT, WEE GOING AFTER PROGESTERONE RECEPTORS AN PR POSITIVE CELL TYPES. IF YOU TAKE A NORMAL CONTRAST AGENT LIKE OPTICAL OR P PET AGENT IT WILL LABEL EVERYTHING IN YOUR BACKGROUND AS UNTENABLE. BUT WITH MRI UNLESS YOU HAVE ENOUGH AGENT THERE YOU WON'T BE ABLE TO DETECT IT. IN THIS CASE THAT'S EXACTLY WHAT WE WANTED BECAUSE THE AGENT IS INJECTED AND ONLY HITS PR POSITIVE NORMAL CELLS AND CANCER CELLS BUT IN THIS CASE UNTHERE'S ENOUGH ACCUMULATION OF AGENT UP REGULATION YOU CAN'T DETECT IT. IN THIS CASE LOOKING AT POSTOP TWO HOURS POSTOP THIS IS WHERE THE AGENT HAS BEEN IN THE PR POSITIVE CELLS AND THE OPPOSITE SIDE IS NOT DETECTABLE. HERE IS A CASE THE LACK OF SENSITIVITY HELPS BECAUSE IT'S HITTING NORMAL AND PR UP REGULATED CELLS BUT IN THE CASE THAT WE WANTED TO DETECT WAS ONLY WHEN THERE WAS UP REGULATION OF SIGNIFICANT CONCENTRATION THAT'S A TARGETED WAY TO APPROACH THIS. THESE ARE THE EXCISED OVARIES WHERE YOU CAN SEE CONTRAST ENHANCEMENT BASED ON THAT AGENT. WHAT ABOUT NON-TARGETED? THIS ONE SURPRISED US, CAME OUT OF NOWHERE, I WAS WORKING WITH BRIAN HOFFMAN, THESE ARE PORFORIN LIKE DERIVATIVES WITH GADOLINIUM, HE TOOK SUBCUTANEOUS TUMORS THAT HAD RFP SO YOU CAN SEE THEM THERE, WE INJECTED OUR CONTRAST AGENT AND WHEN YOU CO-REGISTER, LOOKS LIKE AGENT ONLY GOES TO THOSE CELLS. LDL RECEPTOR UPTAKE, WE DID A FIVE HOUR TIME COURSE, 24, 42 AND 48 POST. THIS IS INJECTION LOCALIZING THE TUMOR OVER TIME AND ONLY IN THE TUMOR. NOTICE THE OTHER SPOTS HERE, WE WESTERN SURE WHAT THOSE WERE AFTER EXCISE -- AFTER ANALYSIS AND CELLULAR ANALYSIS TURNS OUT THOSE ARE THE METS FROM PRIMARY A. SO THIS IS A NON-TARGET ATE PREACH, NO TARGETING DOMAIN ON IT THAT'S BOTH OPTICAL AND MRI SIMULTANEOUSLY. SO ANOTHER NICE EXAMPLE OF NON-TARGETED. MOVING TO SIGNAL AMPLIFICATION AND NANOPARTICLES. THE REASON IS BECAUSE YOU CAN GET A LOT OF SIGNAL. SMALL MOLECULE FROM 4 TO 85 TO 100 IN TERMS OF RELACKSIVETY, WHICH IS GREAT. BUT WHERE WE WANT TO GO IS HIGHER THAN THAT. AS I SAID, MOVING AWAY FROM IRON AS MANY HAVE AND CERTAINLY FDA AS WELL. AND FOCUSING MORE OR LESS ON GOLD AND CARBON. SO I WILL TAKE ADVANTAGES HERE, YOU CAN CELLULAR AND SUBCELLULAR TARGET, MULTI-FUNCTIONAL BIOACTIVATE AND SO THE PARTICLE IS INERT ENOUGH YOU CAN DO THESE THINGS IN ONE PARTICLE AND MILTLY APPLICATIONS THAT I HOPE I CAN GET TO THOSE. SO FIRST EXAMPLE OF THIS ON GOLD. WHAT I CITED EARLIER, THIS IS A PROJECT WITH CHAD MURKI WORKING WITH GOLD PARTICLES. PIECES OF DNA WITH OPTICAL AGENT AT THE END. WE DECRATE WITH A LOT OF GAD, THAT MEANS PER GAD WE GET ABOUT 15 PER GAD THEN WE ADD THIS AND MAKE A PARTICLE THAT IS PRETTY VERY HAIRY GOLD NANOPARTICLE WITH DNA, THIS IS HOW WE DO IT SYNTHETICALLY. TERMS OF RELACKSIVETY, 60 MEG HERTZ 1.5T RELACKSIVETY, THAT PARTICLE IS 6700. SO JUMPING FROM FOUR TO 6,000. THAT MEANS A LOT IN TERMS OF SENSITIVITY AND LONGEVITY. MORE IMPORTANTLY FOR THOSE OF YOU FAMILIAR, AS YOU GO UP WITH T-1 AGENTS 60 MEG HERTZ, TRADITIONALLY THE CLINICAL, WE GO OUT TO 600 MEG HERTZ, 14.1T OUR RELACKSIVETY AT T THAT STAGE ARE 1800. THAT'S A DIFFICULT THING TO DO AT THOSE HIGH FIELD STRENGTHS SO WE'RE HAPPY ABOUT THAT. THESE ARE CONCENTRATIONS IN PHANTOMS WE USE, WE'RE STARTING TO USE THESE IN STEM CELLS, COLLABORATING WITH A NUMBER OF GROUPS TO TAKE THESE PARTICLES AND DO LONG TERM FAKE MAPPING OF CELLS EXVIVO AND IN VIVO. ONE BIG POWER HOUSE OF THESE -- BACK FOR A SECOND OF THESE FEASIBLE PENETRATE -- THESE WILL PENETRATE ANYTHING SO LEARNING MORE ABOUT THAT, CHAD'S WORK SHOWS HOW FAST THESE ARE TAKEN UP BY CELLS. AND CROSSING THE BLOOD BRAIN BARRIER. SO WE ARE EXCITE ABOUT THE BLOOD BRAIN PLATFORM. WE HAVE TAKEN PARTICLES AN INJECTED THEM, THIS IS A MOUSE BRAIN, WE DIDN'T KNOW WHERE THE TUMOR WAS, WE WERE ASKED TO MAP BASED ON PROFUSION. SO WE INJECTED PARTICLES AT SUBMICROMOLAR QUANTITIES AND ASKED COULD WE GET CONTRAST ENHANCEMENT. THIS IS THE TUMOR THAT WE LOCATED POST INJECTION. SO THESE ARE VERY INERT GOLD PARTICLES WITH A LOT OF GADOLINIUM AND THEY HAVE NO TOXICITY THAT WE CAN MEASURE WHATSOEVER. AND THEY WORK WELL. CARBON. THIS SURPRISED US, I WORKED WITH DEAN HO AT NORTHWESTERN, NOW AT UCLA. I LIKE THIS PROCEDURE BECAUSE THE NANODIAMONDS HE MAKES ARE BY DEAF NATION TECHNIQUE, READ THE FIRST SENTENCE IT SAYS OBTAIN 3.2 POUNDS OF C-4. FOR A CHEMIST TO GRAB HOLD OF PAPER THAT SAYS BLOWN UP, TAGETES US EXCITED. THE MAGIC IS SIZE DISTRIBUTION DOWN TO FIVE NANOMETERS. WHAT IS THE SURPRISE? WE TOOK NORMAL GADOLINIUM COMPOUNDS, RELACKTIVETY IN FOUR. WHEN ATTACHED TO THE NANODIAMOND NAY WENT FROM 4 TO 60 PER GAD. THAT'S FOUR TO 60 PER GAD. SO SEVERAL HUNDRED ON A SINGLE PARTICLE YOU CAN IMAGINE INTO THE 4,000 OR 10,000 RANGE VERY QUICKLY. I CAN ONLY SAY THAT WE PUBLISHED WORK ADDING DOXORUBICIN AND GAD NANOPARTICLES, AND WHEN PLACED ON SKIN WE CAN FATE MAP THEM WITH GADOLINIUM SO IT'S A GREAT EXAMPLE. SO I WON'T HAVE TIME THE TALK ABOUT NEW DISCOVERY CALLED ADDING GADOLINIUM TO PARTICLE AND WHAT WE'RE ABSOLUTELY BLOWN AWAY BY IS UPTAKE OF THESE MATERIALS, WE CAN EXPLAIN. IT'S EXTRAORDINARY. FUNCTIONAL IMMANAGING AND GIVE YOU TWO -- IMAGING AND TWO EXAMPLES SO SIZE THIS UP. WE SPENT TIME 15 YEARS AGO MAKING ENZYMATIC REPORTSERS FOR AGENTS. I WON'T GET A CHANCE TO TALK ABOUT THOSE BUT I WANT TO MENTION WORK ON CALLS YUM, AND HAVE TO SKIP THE ZENC. THE FIRST AGENT WAS A SINGLE MOLECULE WITH A DOMAIN THAT WOULD ALLOW CALCIUM TO BIND AND WHEN IT WASN'T BOUND THE AGENT WAS OFF STATE BUT WHEN IT WAS BOUND IT TURNS ON, WE HAD A TRANSDUCTION DOMAIN AND THEN XENOPUS EMBRYOS. TOT, TOP, MID LINE -- THIS IS THE CONTROL, WHERE AGENERAL WAS INJECTION AND NOTHING. IT'S PICKING P BACKGROUND CALCIUM. THIS IS TAKEN IN A MILLISECOND SLIDE SO MR JUST AFTER FERTILIZATION, SO A MILLISECOND AFTER FERTILIZATION. INJECTED IN THE PAIN WE CAN TRACK AND USE THIS TO TRACK SEIZURES SO THIS IS AN MR IMAGE OF SEIZURE IN PROCESS MEASURING THE CALCIUM CONCENTRATION. SUPPOSED TO GET 15 MINUTES. I HAVE 16 MINUTES AND FOUR SECONDS. SO FOUR MILLIMOLAR TO 6700 WHICH A NICE JUMP. WHAT DO WE NEED TO DO NOW? CONNECT WITH THOSE FOLKS THAT ARE OPT FRONT LINES. SUCH ADS MAREN SHOWED EARLIER ZINC AGENTS. WE NEED TO REACH AND TAKE SOME OF THESE TO THE FINISH LINE. IN ORDER FOR THESE TO BE FDA APPROVED THEY HAVE TO BE TESTED. IN ORDER TO BE TESTED SOMEBODY HAS TO GET APPROVAL AND REIMBURSEMENT. AND IN THIS POINT I SEE THE BEST BARRIER IS FOR THE KINDS OF COMPOUNDS THAT WE'RE MAKE HEARING WHICH ARE GREAT FOR BASIC SCIENCE AND MIGHT BE TRANSLATABLE SOME DAY, THE QUESTION IS WHO IS GOING TO REIMBURSE FOR THEM. THE ANSWER IS IN THIS STATE OF HEALTHCARE, I DON'T KNOW WHO. SO MANY CHALLENGES REMAIN. OUR FINAL SLIDE FOR IMAGING CENTER AND NEW HD SCREEN WHICH IS IN THREE DIMENSIONS, 30 FEET LONG. AND 12 1/2 FEET HIGH. WITH THAT I'LL STOP. [APPLAUSE] >> IN THE INTEREST OF TIME AT THE END OF THE SESSION WE'LL HAVE A DISCUSSION PANEL WITH SPEAKERS FROM THE FIRST AND SECOND SESSION. SO THE SECOND SPEAKER IS CHESTER MATHIS, UNIVERSITY OF PITTSBURG TALKING UNMET NEEDS AND PET IMAGING FOR NEURODEGENERATIVE DISEASES. >> THANKS. THANK YOU. PLEASURE TO BE HERE. A LOT OF ME TALK WILL OVERLAP WITH THAT OF KIRK, THAT'S A GOOD THING BUT I COME FROM A SLIGHTLY DIFFERENT PERSPECTIVE. I'M A RADIO PHARMACEUTICAL CHEMIST, NOT A CLINICIAN. SO BEFORE I START, I WANT TO MENTION A DISCLOSURE. I HAVE A CONFLICT OF INTEREST ABOUT TWO COMPOUNDS BRIEFLY IN THIS TALK, PIB AND (INDISCERNIBLE) BECAUSE OF UNIVERSITY OF PITTSBURG HAS A LICENSE AGREEMENTS WITH GE HEALTHCARE. TWO TOPICS, I'M GOING THE TALK ABOUT THE NEED FOR NEUROPROTOOPOTHY AND ALPHA SYNUCLEIN AND NEURAL INFLAMMATION. SO THIS IS A VIN DIAGRAM SIMILAR TO WHAT KIRK SHOWED, I LIKE MY COLOR COMBINATION BETTER THAN KIRKS BUT NONETHELESS YOU BE THE JUDGE BUT WE SHOW THE SAME THING. WE GOT THEM IN THE RIGHT PLACE, I ADD A FEW EXTRA LITTLE PIECES SAME IDEA WITH PROTOOPATHYS WITH AMYLOID LIKE COMPOUNDS. THAT CAUSE CLINICAL DISORDERS. WHAT THE FIELD HAS WANTED MANY YEARS ARE SELECTIVE AL SYNUCLEIN AS KIRK DESCRIBED. OUR EFFORTS AND THOSE OF THE FIELD HAVE BEEN ENCUMBERED BECAUSE MOST HISTOLOGIC DICE BACK 50 YEARS OR MORE ARE NON-SELECTIVE. THEY BIND TO EXTENDED BETA PLEATED SHEET WHICH ALL THE AMYLOID AND AMYLOID LIKE COMPOUNDS CONTAIN. SO THEY WERE NON-SELECTIVE FOR AL L FA SYNUCLEIN, TAU AND A BETA AND DEVELOPED A LIGAND DEVELOPED FOR ONE O OTHERS WAS A CHALLENGE TO THE FIELD. BILL CLUNK UNIVERSITY OF PITTSBURG AND I LOOK AT NUMBER OF HISTOLOGIC DYES ONE WHO STRUCTURE IS SHOWN HERE IS (INDISCERNIBLE) THIS ALSO IS A NON-SELECTIVE DYE FOR EXTENDED SHEETS, NOT A REAL HIGH AFFINITY AS YOU CAN SEE AMYLOID BETA, TAU STRUCTURES AND ALPHA SYNUCLEIN BUT WE STARTED WITH THAT AS BASIS AN REMOVED THE CHARGE FROM THE COMPOUND TO MAKE A NEUTRAL LIPOPHYLIC COMPOUND, TO GET INTO THE BRAIN. SO WE WERE LOOKING FOR A NEUTRAL LIPOPHIL,C COMPOUND THAT BIND THE BETA SHEATHES. ONE FIRST SURPRISE TO US WAS THAT THE AFFINITY OF THIS COMPOUND FOR A BETA WAS TWO ORDERS OF MAGNITUDE GREATER THAN PARENT COMPOUND. BUT EVEN THE GREATER SURPRISE WAS THAT IT BOUNCED SELECTIVELY ONLY TO A BETA. SO WE DEVELOPED AND LIE BAND FROM A NON-SELECTIVE PARENT WE WAS VERY SELECTED FOR HIGH AFFINITY FOR AGGRAVATED A BETA AND DIDN'T EXPEND TO OTHER SHEETS. SINCE THAT TIME, THE FEEL HAS GONE ON, CARBON IS NOT A GOOD RADIONUCLIDE FOR DISTRIBUTION AND CLINICAL USE WITH THE 20 MINUTE HALF LIFE AND THE FIELD DEVELOPED OTHER F-18 LABELED COMPOUNDS ANALOGOUS TO THE PEB SELECT FORD AGGRAVATED A BETA, FOUR WHICH ARE IN CLINICAL TRIALS ONE WHICH IS APPROVED BY THE FDA SHOWN HERE. (INDISCERNIBLE) A LABELED PIP COMPOUND, TWO COMPOUNDS DEVELOPED BY AVID, (INDISCERNIBLE) AND RECENT COMPOUND DEVELOPED BY ASTRA ZENECA. AN EXAMPLE OF ASTRA ZENECA COMPOUND IN HUMAN STUDIES PROBABLY THE LOWEST BACKGROUND SIMILAR TO PIB AN CHARACTERISTICS VERSUS AGE MATCH ELDERLY CONTROL SHOWN IN GENERAL NUCLEAR MEDICINE PAPER LAST YEAR. THE FIELD DEVELOPED SELECTIVE AGENTS AND THEY HAVE GONE INTO CONTRACTS ONE, AMYLOID COMPOUND IS APPROVED BY THE FDA. LAST YEAR, TWO OTHERS HAVE IN CLINICAL TRIALS, IN NDA NEW DRUG APPLICATIONS SUBMITTED TO THE FDA, WAITING FOR FDA RULING ON THOSE COMPOUNDS. A THIRD -- THE FOURTH COMPOUND IS IN PHASE 3 CLINICAL TRIALS, THE AS TRAY SENECA COMPOUND, THEY EXPECT IN PHASE 3 TRIAL NEXT YEAR. THE STATUS IS MCS HAVE REVIEWED COVERAGE FOR REIMBURSEMENT OF AGENTS AND IT'S RECOMMENDED THAT FURTHER STUDY BE DONE PRIOR TO IMPROVING REIMBURSEMENT TO DEMONSTRATE PATIENT OUTCOMES THAT'S A 30 DAY COMMENT PERIOD FOR RECOMMENDATIONS 30 DAYS ENDS TODAY SO YOUR COMMENT TO CMS REGARDING RECOMMENDATIONS TODAY IS THE LAST DAY OF THAT COMMENT PERIOD. WHETHER OR NOT USEFUL CLINICALLY AND REIMBURSED, THEY'RE PROVEN VERY USEFUL IN DEVELOPING ANTI-AMYLOID THERAPIES. AS KIRK MENTIONED, THE FIELD MOVED FROM TREATING ALZHEIMER'S DISEASE[LdÖ TO TREATING PRE-SYMPTOMATIC SUBJECTS. THESE COMPOUNDS WILL BE USED IN THOSE CLINICAL TRIALS, THREE UNDERWAY PRESENTLY TO IDENTIFY SUBJECTS WITH BETA AMYLOID IN THE BRAIN WHO ARE PRE-SYMPTOMATIC FOR ALZHEIMER'S DISEASE HAVE NO CLINICAL SYMPTOMS AND SOME WILL BE TREATED, SOME WILL NOT BE TREATED. ONE CAN SEE WHETHER THE AMYLOID CASCADE HYPOTHESIS IS CORRECT OR NOT WHEN STUDIES FINISH IN 3 TO 5 YEARS. SO A BETA SEEMS TO BE TAKEN CARE OF. SELECTIVE AGENTS FOR A BETA. WHAT ABOUT TAU? SELECT AID GENTS FOR TAU? YOU CAN TAKE A NON-SELECTIVE AND MAKE ONE FOR THE SHEATHE STRUCTURE, HOW ABOUT TAU? KIRK MENTIONED THE FRONTAL TALL TEMPORAL DIMEN HAS, CHRONIC TRAUMATIC ENCEPHALOPATHY THERE AS WELL BECAUSE HIGH TAU CONCENTRATION. WHAT ABOUT TAU AGENTS? THERE'S RECENT WORK IN THE FIELD. AND I WANT TO START WITH THIS SLIDE NEW COMPOUNDS THIS LAST YEAR SHOWING PROMISE IN THIS REGARD, SEM,ANS HAD A PROGRAM PURCHASED BY LILY RECENTLY, TWO COMPOUNDS SHOWN ON THIS SLIDE FOR LEVEL COMPOUNDS WHICH HAVE REASONABLY HIGH SELECTIVITY FOR TAU, 30 FOLD MORE SELECTIVE. ONE COMPOUND WHICH WAS RECENTLY PUBLISHED IS SHOWN HERE, T 807, WHICH DOES APPEAR IN AD SUBJECTS TO REGIONS OF THE BRAIN POSTMORTEM ANALYSIS TAU CONCENTRATIONS, MILD ARCD SUBJECT SOME SIGNAL IN CORRECT REGIONS TO BRAIN, MORE SIGNAL IN SEVERE AD SUBJECTS, NOT MUCH SIGNAL IN HEALTHY CONTROLS OR MCI SUBJECTS. ANOTHER GROUP IN JAPAN WORKED ON A SERIES OF COMPOUNDS, PAPER IN JURY ROOM OF MEDICINE A FEW MONTHS AGO, THERE'S A SERIES SHOW IN VITRO BINDING PROPERTIES OF ONE, THE 5105, YOU CAN SEE IT'S ABOUT THAT 30 FOLD SELECTIVITY DIFFERENCE IN BINDING TAU VERSUS AGGRAVATED A BETA. WE WANT A VALUE OF ONE NANOMOLAR, IT APPEARED THE COMPOUND HAS THAT. THE PROPERTIES IN HUMANS RECENTLY BEEN REPORTED, I GOT THIS SLIDE FROM VICTOR (INDISCERNIBLE) AT -- IN MEL BORNE. SO HERE IN THE CENTER PANEL IS AND IN VIVO PET IMAGE OF AD SUBJECTS TWO SIDE PANELS POSTMORTEM STUDY NOT SUBJECT BUT TYPICAL AD SUBJECTS WHERE YOU CAN SEE THE F-18 LABELED 5105 COMPOUND IS BINDING INFERIOR CORTEX WITH ANTIBODY IMMUNOHISTOCHEMISTRY, POSTMORTEM STAIN, THAT CORRELATINGS WELL WITH PROPERTIES IN VIVO AND, THAT'S TAU AND AD, WHAT ABOUT TAU IN OTHER FRONTAL TEMPORAL DEMENTIAS, CORE TALL BASAL DEGENERATION AND PROGRESSIVE KNEW COLOR PALSY. WHAT ABOUT PICK'S DISEASE AS WELL OR CTE? WHAT ABOUT TAU? THAT'S DIFFERENT ISOFORMS, DIFFERENT DEGREES OF PHOSPHORYLATION. WE DON'T KNOW WHETHER TWO COMPOUNDS HOW THEY WILL DO IN TAUOPATHYS, THE YOUR IS STILL OUT. MANY GROUPS AROUND THE WORLD EVALUATE THAT PRESENTLY, WE ARE WAITING FOR THE RESULTS OF EVALUATIONS WE HOPE THEY WILL BE USED BUT YOU HAVE TO WAIT TO SEE IF THEY'RE ARE. THEY BIND TO NEUROFIBRILLARY TANGLES IN ALZHEIMER' DISEASE BUT WHETHER THEY'RE EFFICACIOUS IN OTHERS WE ROLL SEE. ONE AREA KIRK MENTIONED ALSO IS ALPHA SYNUCLEIN, AN AGENT FOR ALPHA SYNUCLEIN, IT WOULD BE USEFUL FOR MANY PURPOSES. THEY'RE PARTICULAR IN PD, DLB AND MULTIPLE SYSTEM ATROPHY. O OUR GROUPS ARE TRYING TO FIND THE NEED TO DO THIS, IN THERAPEUTIC CHARGE -- (INDISCERNIBLE) COUPLE OF DIFFICULTIES IS THAT THE AMOUNT OF ALPHA SYNUCLEIN IS LESS THAN THE AMOUNT OF A BETHAT IN ATE SO THE TARGET DENSITY IS LOWER. ALPHA WHILE PLAQUES ARE EXTRA CELLULAR, IF THE COMPOUND IS LIP POE PHILIC ACROSS THE BLOOD BRAIN BARRIER IT WILL PENETRATE CELL MEMBRANE BUT THAT REMAINS TO BE PROVEN. IT FACES THE DIFFICULTY MANY AGENTS IN THIS AREA ARE NON-SELECTIVE. YOU HAVE TO DEVELOP AN AGENT FOR ALPHA SYNUCLEIN SO THAT'S OOH THE MAIN UNMET NEEDS AND THOSE EFFORTS WILL BE SUPPORTED AND COME TO FRUITION AS MUCH AS A BETA AND TAU SELECTIVE AGENTS COME TO FRUITION. OTHER NEEDS KIRK MENTIONED TDB-43 SELECTIVE AGENT. HUNTINGTON, KIRK DIDN'T MENTION BUT A BETA SHEATHE, HUNTINGTON'S DISEASE THERE'S THERAPIES, ANTI-HUNTINGTON THERAPIES DEVELOPED SO A MARKER WHICH TARGETED HUNTINGTON WOULD BE VERY HELPFUL AS THERAPEUTIC APPROACHES TO TREAT HUNTINGTON'S DISEASE, ANOTHER BETA SHEET STRUCTURE. WILL BE HELPFUL IN (INDISCERNIBLE) DISEASE, AS WELL AS (INDISCERNIBLE) AND OTHER PRION DISEASES SO THERE'S A NUMBER UPHEAVERIAS -- AREAS WITH UNMET NEEDS IN SELECTED PROTOOPATHYS. GOOD PROGRESS IN SOME YEARS IN A BETA AN TAU BUT OTHER TARGETS NEED ATTENTION AS WELL. THE SECOND AREA I WANT TO TALK ABOUT IS IMAGING CNS INFLAMMATION. INFLAMMATION IS A PATHOLOGICAL FEATURE OF MANY DISEASES IN THE BRAIN SOME WHICH ARE LISTED HERE, DETECTING AND MONITORING INFLAMMATION REMAINS A CHALLENGE PERIPHERAL LIRK THERE'S NO RELIABLE CFS MARKER, INSPECT AGENTS HAVE TARGETED OVER 30 YEARS THE TSPO KIRK MENTIONED. THE EXPRESSION OF TSBO TARGET IS LOCATED ON ACTIVATED MICROGLIA. AS RELATIVELY LOW CONSTITUTIVE EXPRESSION IN NORMAL BRAIN TISSUE. PROTOTYPICAL LIGAND OUT THERE FOR NOW 30 YEARS PK 1195. IT'S LABELED CARBON 11 IN MANY STUDIES, INITIALLY THE MIXTURE WAS STUDIED BUT THE ACTIVE NOW USED IN MOST STUDIES. THE CAN KD VALUE FOR BINDING TO THE TSPO SITE IS VARIES BETWEEN TWO AND 20 NANOMOLAR. PK HAS LIMITATIONS DESPITE ITS USE OVER THE PAST 20 YEARS. THE COMPOUND HAS LOW SPECIFIC BINDING SIGNAL. IT IS HIGHLY LIPOPHYLIC AND PROVIDES BACKGROUND TO LOW BINDING SIGNAL. THE TEST VARIABILITY IS QUITE POOR. IN PK IT'S DIFFICULT TO INTERPRET IN THE CONTEXT OF THE DISEASE PATHOLOGY, THAT IS SIGNAL FOR EXAMPLE CORRELATED WITH AMYLOID LOAD IN MCI AND AD SUBJECTS. SO THAT HAS THE FIELD TO TRY TO DEVELOP OTHER AGENTS TO TARGET TSPO WHICH HAVE IMPROVED PROPERTIES RELATIVE TO PK-1195. THIS IS NOT A COMPLETE LIST BUT A LIST OF NUMBER OF COMPOUNDS INVESTIGATE AND REMAIN UNDER INVESTIGATION. THE HOPE IS SPECIFIC BINDING SIGNAL IS GREATER, BACKGROUND LOWER, IT WILL BE USEFUL FOR IMAGING ACTIVATED MICROGLIA. THIS SLIDE GIVES AN IDEA OF WHERE THE STATE-OF-THE-ART IS. SO I MENTIONED PK ISN'T A GREAT SIGNAL, MS SUBJECTS FROM 2000 BY (INDISCERNIBLE) AND CO-WORKERS. IN MS, AND THE WHITE MATTER OF MS VERSUS CONTROL SUBJECTS, SMALL SIGNAL, NOT SIGNIFICANT DIFFERENCE IN THE THALAMUS AND BRAIN STEM BUT INDIVIDUAL SUBJECTS HE WAS ABLE TO TEASE OUT Z SCORES FOR INDIVIDUALS BUT GROUP DIFFERENCES WEREN'T SIGNIFICANT. IT'S REPORTED IN THE SAME SIMILAR GROUP OF SUBJECTS, MS SUBJECTS NEMH HERE INTRAMURAL PROGRAM REPORTED RESULTS WITH THIS PBR-28. YOU CAN SEE IF THEY SIMPLY LOOKED AT THE SIGNAL AND COMPARED WHITE MATTER SIGNALS IN MS VERSUS THE HEALTHY CONTROLS, THERE WAS NO SIGNIFICANT DIFFERENCE IN SIGNAL BUT THEY WERE ABLE USING WHITE TO GRATE MATTER TO GET A P VALUE OF .02 BUT LOOK AT THE INDIVIDUAL DATA POINTS YOU SEE OVERLAP. NOT A HUGE DIFFERENCE IN MEAN VALUES BETWEEN THE TWO GROUPS. A NEUROPATHOLOGIST TELLS YOU MS IS ONE DISEASE, THERE SHOULD BE PLENTY OF SIGNAL IF YOU'RE LOOKING FOR INFLAMMATION. YOU CAN CERTAINLY SEE IT HUGE SIGNALS POSTMORTEM SO BETTER THAN THIS ONE WOULD EXPECT IN COMPARING MS SUBJECTS TO CONTROL SUBJECTS. ANOTHER PROBLEM WITH THESE NEW AGENTS IS POLYMORPHISM, AND WHAT'S BEEN FOUND IS THAT POLYMORPHISM IN THE TSPO GENE, 10% SUBJECTS DO NOT EXPRESS BINDING SITES TARGETD BY LIGAND. 25% ARE HETEROZYGOTES SO THEY HAVE MIXED AFFINITIES. 65% ARE HOMOZYGOTES WITH PARTICULAR POLYMORPHISM AND THEY EXPRESS GOOD BINDING TSPO SITES YOU CAN SEE LOOKING ACROSS FIVE AGENTS AND THAT NEW CLASS WHICH WHAT YOU SHOULD SEE IS A SINGLE LINE, SOMETHING THAT LOOKS LIKE THIS, WHICH DOESN'T SUFFER FROM THIS POLYMORPHISM BUT ALL THESE NEW LIGANDS THAT I MENTION PREVIOUSLY SUFFER FROM THE POLYMORPHISM, MAKES STUDIES DIFFICULT TO INTERPRET. SO OVER PAST THREE DECADES, THERE'S NEW LIGANDS BUT MODEST ADVANCES IN THE FIELD HAVE BEEN REALIZED. THIS COULD BE RELATED RATHER THAN PROPERTIES OF RADIO LIGAND, COULD BE RELATED TO PROPERTIES OF THE TARGET ITSELF, THE TSPO. MY HOPE IS FUTURE RESEARCH PLACES MORE EMPHASISSEN NEW TARGETS OTHER THAN TSPO FOR CNS INFLAMMATION. SOME EXIST HERE POSSIBILITIES. THERE ARE MANY IN THIS CLASS BUT AS RESEARCH GOES FORWARD WE'LL GET A MORE ROBUST TARGET WHICH IS A BETTER INDEX OF NEUROINFLAMMATION. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> OUR THIRD STATION IS STANISLAV EMELIANOV, WHO WILL TALK ABOUT ULTRASOUND PROBE DESIGNS FOR MOLECULAR BASED IMAGING. >> GOOD MORNING. THANK YOU FOR THE INVITATION. TO PRESENT. I WAS ASKED THE TO TALK ULTRASOUND SO I THOUGHT I'LL START BIG PICTURE. HERE IS PROBABLY ANOTHER SURPRISE FOR YOU. THE PET INSPECTOR NUCLEAR IMAGING CAN REALLY ASSESS NO REGULAR COMPOSITION OF TISSUE BUT OTHER TECHNOLOGIES CANNOT. PET BY DEFINITION USING CONTRAST AGENT OR MOLECULAR PROBES DON'T HAVE TO SO IN ORDER TO BRING THOSE TECHNOLOGIES ULTRASOUND INCLUDED TO MOLECULAR IMAGING WE HAVE TO INTRODUCE CONTRAST AGENTS. HERE IS THE FIRST CHALLENGE THAT COMES IN. ANATOMICAL STRUCTURES WE'RE HAPPY WITH MILL MILIMY TEAR SUBMILIMETER RESOLUTION. SOMETHING DEEP AT THE MOLECULAR LEVEL YOU HAVE TO CROSS SIX ORDERS OF THE MAGNITUDE IN TERMS OF SPATIAL SCALE SO NOT AN EASY TASK AND WHY WE SEE NOT EVERY IMAGING TECHNOLOGY CAPABLE OR IMMEDIATELY CAPABLE OF MOLECULAR IMAGING. IT DOES A GREAT JOB MORE E FOE LOGICAL IMAGING, TO IMAGE THE MAIN STRUCTURE, LIMITED BUT DECENT FUNCTIONAL IMAGING WITH THE EXAMPLES WOULD BE DOPPLER ULTRASOUND, ELASTICITY IMAGING BUT WHERE IT SUFFERS FROM MOLECULAR AND CELLULAR IMAGING BECAUSE OF THE CONTRAST AGENTS. THEY NORMALLY COME US IN TERMS OF CONTRAST AGENTS ARE RELATIVELY LARGE, THEY ON THE MICROMETER SIZE IN CERTAINLY WITHIN LIMITED IN TERMS OF OBLIGATIONS TO VASCULAR COMPARTMENTS. SO THAT'S A CHALLENGE AND PROBLEM THAT NEEDS TO BE OVERCOME. AND WHAT I WILL TRY TO CONVINCE YOU TODAY IN THE REMAINING 18 MINUTES, ULTRASOUND HAS THE POTENTIAL TO CROSS THE SPATIAL SCALE AND WILL BE DONE THROUGH TWO INNOVATIONS. ONE IS MULTI-WAVELENGTH ULTRASOUND SO MULTIPLE WAVELENGTHS OR SOURCES OF ENERGY, YOU NAME IT AND THE SECOND IS TO AUGMENT ULTRASOUND WITH SCALE CONTRAST AGENTS THOUGH THE TYPICAL MOST POWERFUL CONTRAST AGENT IN ULTRASOUND EXISTS AT THE MILLIMETER SCALE SO THREE ORDERS OF MAGNITUDE DOWN. SO ONE -- I CANNOT GIVE ALL THE EXAMPLES BECAUSE IT'S ONLY ONE DAY WORKSHOP, BUT WHAT I WILL FOCUS ON IS A RELATIVELY NEW TECHNOLOGY CALLED (INAUDIBLE) WHICH WE WILL COMBINE WITH ULTRASOUND. SO THOSE ARE TWO APPROACHES, FOR ACOUSTICS AND NOT CONTRAST AGENT SPECIFIC FOR THIS ULTRASOUND FOR ACOUSTIC TECHNOLOGY. IF YOU'RE BUILDING THE SYSTEM THE EASIER APPROACH IS TO TAKE ULTRASOUND SYSTEM IN GRAY, IN HERE, AND THEN ADD TUNEABLE PULSE LASER AND LITTLE BIT PROCESSING THAT WOULD EXIST IN ULTRASOUND SYSTEM AND YOU GOT YOURSELF TWO IMAGING SYSTEM FOR THE PRICE OF ONE AND A HALF. SO AS YOU INTRODUCE TUNEABLE LASER WITH IMAGING SYSTEM THE OTHER THING YOU NEED TO DO IS INTRODUCE LIGHT DELIVERY SYSTEM WHICH NORMALLY WOULD EXIST IN TERMS -- IN FORM OF OPTICAL FIBERS, THAT WILL SURROUND THE ULTRASOUND CLINICAL TRANSDUCER WE USE IN CLINICAL PRACTICE. THE WAY THIS TECHNOLOGY WORKS IS WE START WITH WITH COMBINE SYSTEM, IRRADIATE TISSUE WITH SHORT PULSE. NANOSCALE LEVEL, NANOMETER NANOSECOND DURATION PULSE. OPTICAL ENERGY WILL BE ABSORBED. THAT'S WHAT ABSORBERS DO, THAT ELECTROMAGNETIC ENERGY IS CONVERTD TO HEAT OR THERMAL. SINCE EXITATION IS VERY FAST IT WILL UNDERGO THERMAL EXPANSION IN ANYTHING RAPIDLY EXPANDING, IT WILL PRODUCE BROADBAND PRESSURE WAVES CENTERED AROUND THE ABSORBER BUT THEN WILL BE UNIDIRECTIONAL WAY SO ALL WE HAVE TO DO IS INTRODUCE YOU WANT TRAY SOUND CLINICAL TRANSDUCER OR IMAGING PROBE BUT SINCE WE HAVE THE TRANSDUCER WE MIGHT FOLLOW THE FIRST IMAGE TECHNIQUE WITH A TRADITIONAL PULSE ECHO ULTRA SON IMAGING SO TECHNOLOGY IS SIMPLE, ANALOGOUS GHOST TO THE ULTRASOUND. SAME ECHO EXCEPT WE SEND ULTRASOUND TO THERMAL EXPANSION OF TARGET AND GENERATE PRESSUREWAYS SAME AS ULTRASOUND. SO THIS IS NOT A SCIENTIFIC DREAM. THERE ARE COMMERCIAL IMAGING SYSTEMS NOW AVAILABLE. THE EXAMPLE IS VIVO LASER PRODUCED BY VISUAL SONICS. THIS COMBINES ULTRASOUND AND ACOUSTICS, THIS WOULD BE TYPICAL ULTRA SON SCANNER FOR SMALL ANIMAL IMAGING. THIS IS THE LASER SOURCE AND THEN OBVIOUSLY OPTICAL LIGHT DELIVERY AND ULTRASOUND ARE INTEGRATED HERE. HOWEVER, TWO MORE ACOUSTIC IMAGING SYSTEMS, ONE IS BY (INAUDIBLE) AND ONE IS BY ITHERA MEDICAL. FOR ACOUSTIC IMAGING OR COMBINATION OF ULTRASOUND AND FOR ACOUSTICS WAS FIRST INTRODUCED TO LOOK AT ENDOGENOUS CONTRAST. ONE STRONG IS HEMOGLOBIN, YOU CAN SEE OPTICAL ABSORPTION IS STRONG OF THIS MOLECULE OR COMPOUND. BUT THE POINT ON THE SLIGHT IS DIFFERENT THE, IF YOU WANT TO IMAGE AT DEPTH, 3 TO 5-CENTIMETERS, WE'RE NOT TALKING ABOUT MICRONS AN MILLION METERS YOU PICK YOUR WAVELENGTH THIS OPTICAL RANGE THAT YOU ENSURE SIFT PENETRATION OF SCATTERED LIGHT TO TISSUE. WHAT WE WANT TO DO IS MOLECULAR IMAGING BECAUSE I BELIEVE THIS IS WHERE IMAGING MAKES IMPACT. WE HAVE TO INTRODUCE CONTRAST AGENTS. TWO CHOICES. YOU CAN GO WITH METAL GOLD NANOPARTICLES OR OBSTACLE DYES PICTORIALLY SHOWN HERE, THIS WOULD BEu/j SIMPLE GOLD NANOSPHEARS, WE CAN CHANGE ASPECT RATIO OF THOSE. AND WHAT HAPPENS WITH ISOTROPIC STRUCTURES NANORODS OR NANOPLACE TRIANGLES, PRISMS, THE PEAK ABSORPTION WILL CHANGE DEPENDING ON SIZE AND RATIO, AND THEREFORE YOU CAN TUNE IT. NOW, THIS IS A QUICK SUMMARY OF THE DIFFERENCES BETWEEN NANOPARTICLES IN TISSUE AND DYE. FIRST NANOPARTICLES ARE TUNEABLE, I CAN PUT) ANYWHERE IN THE DESIRED OPTICAL RANGE. NUMBER TWO, THERE ARE HIGHLY EFFICIENT PREVIOUS SPEAKERS TALKED ABOUT SIGNAL AND AMPLIFICATION BY DOING NOTHING SIX ORDERS OF MAGNITUDE HIGHER THAN TISSUE AND FIVE ORDERS MAGNITUDE HIGHER THAN OPTICAL DYES BUT THIS HAPPENED TO BE THE IDEA CONTRAST AGENT FOR ACOUSTIC IMAGING YET THAT'S EXCITING TO DO MOLECULAR CELLULAR IMAGING. SO VARIETY OF CONTRAST AGENTS TO SYNTHESIZE OR POSSIBLY -- I WANT TO MOVE TO A CLINICAL PROBLEM, DETECTION AND CHARACTERIZATION OF SENTINEL LYMPH NODE. THIS PROJECT IS ACTUALLY FUNDED BY (INAUDIBLE) MAKING GOOD PROGRESS ON THAT. SO IN THIS PARTICULAR CASE, ONCE THE PATIENT IS DIAGNOSED WITH PRIMARY TUMOR THE QUESTION BECOMES DID THE THANK YOUER MORE METASTASIZE. THIS TUMOR HEAD AND NECK SQUAMOUS CONSIDERS KNOW MA IN THE LYMPHATIC SYSTEM, THE QUESTION BE BECOMES WHERE IS THE SENTINEL LYMPH NODE LOCATED THAT THE TUMOR IS TRAINING TO, STARTING WITH. SECOND QUESTION WOULD BE ARE THERE CANCER CELLS IN THE SENTINEL LYMPH NODE. SO CURRENTLY WHAT WE DO IS RELATIVELY BRUTAL TECHNOLOGY. WE MIX DYE WITH RADIO ACTIVE TRACER WE INJECT NEAR THE TUMOR, ALLOW IT TO DRAIN AND USE NUCLEAR MEDICINE TO DETECT THE LOCATION OF THE LYMPH NODE AND THEN BIOPSY, I HAVE BEEN SESSION OPENING [EXPLETIVE] TRACTION OF TISSUE TO SAMPLE FOR THE PRESENCE OF MICROMETASTASIS. IF OUTCOME IS POSITIVE THE LYMPH NODE STRUCTURE ALREADY REMOVED NEAR THE TUMOR. VERY EFFECTIVE TECHNOLOGY BUT INVASIVE, IT REQUIRES MULTIPLE EXPERTS TO BE PRESENT ON SINE, RAID ACTIVE TRACERS ARE NOT SOMETHING YOU CAN USE AT HOME. AND IT WILL TAKE UP TO TWO WEEKS TO FIND THE ANSWER. IMAGINE YOU ARE THE PATIENT DEALING WITH THE DISEASE WHAT WOULD BE THE ANXIETY LEVEL, IF YOU HAVE TO WAIT SO LONG. WE SUGGEST WE CAN USE ULTRASOUND IN ACOURSICS TO SOLVE THE PROBLEM. EXAMPLES, THERE'S MANY APPROACHES BUT THE EXAMPLE I WILL GIVE YOU WILL UTILIZE NANOSPHERES WITH PEAK ABSORPTION 532 NANOMETERS ROUGHLY 530 NANOMETERS. WHAT WE'LL DO IS THE SAME TECHNOLOGY. , MAKE COCKTAIL OF DYE BUT TARGETED GOLD NANOSPHERES INJECT SAME WAY NEAR THE TUMOR, ALLOW THAT CONTRAST AGENT TO DRAIN BUT NO LONGER BIOPSY PERFORMED, WE WILL USE ULTRA SOUND GUIDED FOR ACOUSTICS TO IMAGE SENTINEL LYMPH NODE AND HOPEFULLY DETECT CANCER CELLS WITHIN THE NODE. HERE IS NEW CONTRAST AGENT NON-TOXICS IN OUR IMAGING TECHNOLOGY WHICH COMBINES TRAWL SOWN IN ACOUSTICS. THIS IS WHERE AGAIN THERE IS A BILL CHALLENGE IN THE FIELD, I THINK IT'S A COMMON CHALLENGE. HOW DO WE SEPARATE THE CONTRAST AGENT THAT ARRIVED TO THE SCENE. VERSUS THE SAME CONTRAST AGENT THAT INTERACTED WITH THE CANCER CELLS BECAUSE OF TARGETING WE PROVIDED. NO SURPRISE TO ANYONE EPR WILL DELIVER ANY MOLECULES OR PARTICLES IN THE VICINITY OF TUMOR AND EXTRA CELLULAR BECAUSE OF THE LEAKY VASCULATURE SO HOW SEPARATE BY SIMPLE IMMA'AMING THE TWO CASES? THE SOLUTION COMES FROM BIOPHYSICS OR BIOLOGY AND PHYSICS BECAUSE THOSE TWO CASES WILL BE DRASTICALLY DIFFERENT IN THE FIRST CASE, THE NANOPARTICLES WILL BE IN THE VICINITY OF THE CELL THAT CAN BE ON THE MEMBRANE JUST STATISTICALLY SPEAKING. THE NANOPARTICLES WILL LAUNCH ANT RECEPTORS OVEREXPRESSED AT SURFACE OF THE CELL AND ULTIMATELY WILL BE ENDOCYTOSED INSIDE THE CELL. AND FORM VERY TIGHT COMPARTMENTS FULL OF THESE NANOPARTICLES. THAT'S WHY OPTICAL IMAGING YOU CAN SEE DRASTIC DIFFERENCE. THIS COLOR COMES FROM THIS INDIVIDUAL NANOPARTICLES IN THE BACKGROUND, VERSUS NOW YOU SEE THE NICE LABELED CANCER CELLS L WHICH HAVE NANOPARTICLES THAT ARE ENDOCYTOSED. SO IF I TURN THE ULTRA SOUNDS ON, THIS CONTAINS GELATIN IN THOSE CELLS MIXED WITH NANOPARTICLES WITH WITH INDIVIDUAL OR ENDOCYTOSED, WE CANNOT DISTINGUISH THE CASES BECAUSE WE'RE NOT SENSE ACTIVE TO NANOSCALE CONTRAST AGENT BUT WHEN YOU TURN THE LIGHT ONDFIGURATIVE AND PRACTICALLY SPEAKING THE THE SITUATION CHANGES. WE WON'T IMAGE 3532 NANOMETERS BECAUSE WE UNDERSTAND PHYSICS AND BUYOLOGY, WE ACTUALLY ARE GOING TO IMAGE OFF THE RESONANCE, YOU PROBABLY CAN APPRECIATE DRASTIC DIFFERENCE BETWEEN TWO CASES WHERE WE JUST MIX NANOPARTICLES WITH CELLS, WITH IT WILL SIGNAL. WHEN THEY ENTOECYTOSE NANOPARTICLES WE HAVE AMPLIFIED ACOUSTIC SIGNAL FROM THIS SCENARIO. THIS IS FROM WELL KNOWN CUP LINK AN THERMAL CUP LINK DISCOVERED LATER WHICH WILL DRASTICALLY CHANGE THE OPTICAL SPECTRA OF INDIVIDUAL PARTICLES SEARCH AND SEIZURE PARTICLES THAT HAVE BEEN ENDOCYTOSED. THAT CREATES MECHANISM WHICH NANOPARTICLES BECOME NOT JUST CONTRAST AGENTS BUT MOLECULARLY ACTIVATED MONOSENSORS. SO EVERYTHING WORKS IN VITRO THAT WOULD WORK IN VIVO. SO WE STARTED CANCER MODEL THAT WOULD METASTASIZE IN THE LYMPHATIC SYSTEM SO THIS IS FROM MD ANDERSON CANCER SENT HERB, WE INJECTED THE PIE MARE TUMOR 5 NANOLITTER SPHERES, TARGETED IN THE WRONG WAY SO PRIMARY TUMOR IS HERE AND BY DEFINITION THE LYMPHATIC SYSTEM IS LOCATED HERE SO THE LYMPH NODES ARE IMAGING ARE DOWN THE LINE. SO HERE IS THE US TRAY SOUTH SOUND IMAGE YOU CAN SEE THE LYMPH NODE YET YOU CANNOT SEE NEITHER CANCER CELLS NOR NANOPARTICLES AS MENTIONED BEFORE ULTRASOUND IS NOT SENSITIVE TO THAT. I'LL WALK THROUGH THREE GROUPS OF ANIMALS IN FIRST GROUP A WE MADE THE MATCH BETWEEN PRIMARY TUMOR IN TARGETED PARTICLES, THEN TRIED TO FOOL THE SYSTEM, TUMORS ARE HERE BUT PARTICLES ARE WRONGLY TARGETED. THERE WAS NO TUMOR BUT NO MATTER IF YOU INJECT NANOPARTICLES THEY WILL TRAIN LYMPHATICS AND WE INJECT NANOPARTICLES TO SEE WHAT WILL HAPPEN. HERE IS THE COMPARISON BETWEEN ULTRASOUND IN YOU WISH. IN OPTIMAL IMAGING LIKE I SAID, HOPE PROVIDE HIGH RESOLUTION IMAGING IN OPTICS NOT CAPABLE VISUALIZING DEEP STRUCTURES BECAUSE THE LIGHT WILL SCATTER BUT IN OUR CASE WE DONE RELY ON THE LIGHT SCATTERED, WITH RELY ON THE THE ENERGY THAT LIGHT DELIVERS YET OUR DETECTION IS BASED ON ULTRASOUND. HERE ARE THE THREE GROUPS. YELLOW COLOR RESPONSE RESPOND TO NANOPARTICLES THAT WERE ACTIVATED, INTERACTED WITH THE CANCER CELLS. IN THE OTHER TWO CASES WE STILL HAVE PLENTY OF NANOWE SEE NO YELLOW COLOR INDICATING THE INTERACTION DID NOT TAKE PLACE. 3-D IMAGES FROM THE GROUP ONE, WE SEE THE CUT AWAY VIEW, THIS IS THE LYMPH NODE SEGMENTED FROM THE ULTRASOUND. ADDING ACOUSTIC SIGNAL WE SEE SOME FROM BLOOD. LYMPH NODES HAVE BLOOD AND THEREFORE HEMOGLOBIN BUT MORE IMPORTANTLY WE DO SEE NICE SIGNAL FROM MICROMETASTASIS IN THE LYMPH NODE. THIS IS THE TIME SCALE. AS WE INJECT WE CAN IMAGE BOTH SIDES OF THE MOUSE. SO RIGHT AND LEFT LYMPH NODE. THIS HAPPENED TO BE NORMAL IN -- AS A FUNCTION OF TIME WE SEE NO ACOUSTIC SIGNAL COMING FROM INTERACTIVE NANOPARTICLES YET IN THE METASTATIC NODE WE SEE NICE PROGRESSION OF SIGNAL INDICATING ARRIVAL IN AND INTERACTION OF TARGETED PARTICLES WITH THE CANCER CELLS, 3-D IMAGE AND MAYBE MORE ZOOMED IN VERSION OF IMAGE BEFORE AND AFTER INJECTION SO STATISTICCAL ANALYSIS TELLS US IMAGING MICROMETASTASIS AND NOT ANYTHING ELSE SO SIGNATURE GNAT IS RELATIVELY LOW FROM THE OTHER TWO GROUPS. SENSITIVITY AND SPECIFITY IN THIS LIMITED NUMBER OF EXAMPLES. WE CAN USE THE SAME TECHNOLOGY, ULTRASOUND AND ACOUSTICS IN VARIOUS APPROACHES NOT NECESSARILY CANCER RELATED. THIS IS THE IMAGES OF ATHEROSCLEROTIC VESSEL SO YOU SEE THE CROSS SEC OF THE VESSEL. NORMALLY WOULD BE ONLY THAT THIN BUT EVERYTHING ELSE YOU SEE HERE IS DEPOSITION OF THE LIPID WITH MACROPHAGE ACTIVITY. BECAUSE WE CAN USE DIFFERENT WAVELENGTHS IN OUR TECHNOLOGY VERSATILE, WE CAN SIMULTANEOUSLY IMAGE LIPID OR PRESENCE OF THE LIPID, IN MACROPHAGE ACTIVITY WHICH MEANS MACROPHAGES PHAGOCYTOSE NANOPARTICLES. THIS IMAGE, NOBODY HAS SEEN BEFORE SPECIFICALLY SORT OF THE IN VIVO IMAGE OF LIP DECISION, THAT RESULTS WITH DEPOSITION TOGETHER WITH THE MACROPHAGE ACTIVITY T. TWO VESSELS CUT THE VESSEL SHOWING FROM THE INSIDE OUT, YOU CAN SEE COMPLETELY DIFFERENT PICTURE HERE VERSUS THE SECTION NUMBER 2, AND THIS PLAQUE WILL CORRESPOND MORE TO THE VULNERABLE PLAQUE BECAUSE THE MACROPHAGES ARE VERY ACTIVE AT THE SHOULDERS SO THIS PLAQUE IS PRONE TO BE BROKEN AND RELEASE THE LIPID IT CONTAINS INSIDE. NOBODY IS STANDING SO I ASSUME I HAVE 30 MINUTES. I WILL SKIP THIS BUT SHOW UNPLEASANT DISCOVERY WE MADE BUT WE UNDERSTAND WHERE IT'S COMING FROM. SO WE IMAGE THIS PARTICULAR LYMPH NODE FOR TWO HOURS AND WERE SATISFIED BUT THEN WE SAID KEEP THE MOUSE A LITTLE LONGER IN IMAGE MAYBE IN THE 18 TO 24 HOURS. ALL OF A SUDDEN THE SIGNAL ALL OVER THE PLACE. IN 24 HOURS THE TUMOR WON'T GROW AND MICROMETASTASIS WILL NOT EXPAND EXPONENTIALLY SO SOMETHING ELSE IS HAPPENING. WHAT'S HAPPENING HERE IS MACROPHAGES THEY ENDOCYTOSE NANOPARTICLES AND PRODUCE SIGNAL, OUR APPROACH TO SEPARATE WOULD BE TO INTRODUCE SYSTEM WHERE WE MIX NANOPARTICLES OF DIFFERENT TYPES FORM AND SHAPE HOPING TO RESOLVE AND PROVIDE IMAGES OF MULTI-PLEX IMAGES WITH NANOSPHERES VERSUS STEM CELLS L LOADED WITH NANORODS. WE MAKE THEM IN DIFFERENT RATIO IN THIS PHANTOM, WE CAN QUANTIFIBLY DETECT WHAT TYPE OF CELLS AND THEREFORE POSSIBLY PHENOTYPING OF THOSE CELLS WITH CANCER OR ANY OTHER MODEL. IT WORKS IN VIVO. WE HAVE DONE IMAGING UP TO SEVEN DAY AND IT DOES WORK. I'M RUNNING OUT OF TIME BUT I'M GOING TO TAKE MY QUESTION FOR TWO MINUTES. HOW DO WE TRANSLATE THE CLINIC? BIG QUESTION BECAUSE WE'RE DEALING WITH NANOPARTICLE THAT ARE A CONCERN. WE KNOW FROM LITERATURE AND STUDIES IF WE INJECT NANOPARTICLES THAT ARE LARGE THEY GO ALL OVER THE PLACE, INTO LIVER, INTO KIDNEY, SPLEEN, AND ONLY SMALL FRACTION WILL END UP IN TUMOR. BUT MORE IMPORTANTLY, THEY WILL STAY IN THE SYSTEM FOREVER. BASICALLY TATTOOED THE ORGANS PERMANENTLY WITH GOLD NANOPARTICLES. THE OTHER APPROACH IS TO USE PARTICLES THAT ARE ON THE ORDER OF FIVE NANOMETER, AS THEY DELIVER THE SYSTEM WE HAVE THE ABILITY TO CLEAN RENALLY SO THEY WILL BE REMOVED. GOLD NANOPARTICLES IN VIVO? WE'LL TAKE SMALL NANOPARTICLES INTRODUCE AND THEY WILL INTERACT AND ULTIMATELY THEY WILL BE CLEARED FROM THE SYSTEM. IF YOU WANT TO DO IT IN MORE SYSTEMATIC WAY THEN THE APPROACH WOULD BE TO CONSISTING PRIMARY PARTICLES AND AS YOU INJECT THEM THEY FIRST PRODUCE THE SIGNAL TO EXCRETE THEM RENALLY AGAIN SO THAT CONTRAST AGENT WILL BE GONE. I'LL FINISH HERE AND WE'LL HAVE SOME TIME FOR QUESTIONS. THANK YOU. [APPLAUSE] >> SO OUR FINAL TALK IS FROM (INAUDIBLE) -- >> I WAS ASSURED BY THE IT GUY HE WOULD BE HERE TO HOOK THIS UP. HOPEFULLY THIS WILL WORK. MARTIN POMPER. THANKS A LOT, I WOULD LIKE TO THANK DR. LIU FOR INVITING ME. I'M GOING TO TALK ABOUT MULTI-MODALITY MULTI-FUNCTIONAL MOLECULAR IMAGING AGENTS. THIS IS ACTUALLY REPRESENTING 3% MOLECULAR IMAGING AGENTS GIVEN TO ANIMALS OR HUMANS ACCORDING TO THE MOLECULAR IMAGING CONTRAST AGENT DATABASE. WE'RE JUST BEGINNING IN THIS FIELD. MOLECULAR IMAMMING IS A BIOLOGY DRIVEN ENTERPRISE, WE HAVE BIG FOUR MODALITIES. THESE MODALITIES ARE COMPLIMENTARY TO ONE ANOTHER WHAT THEY CAN DO. THEY'RE ALSO DIFFERENT IN TERMS OF SENSITIVITIES, WE'RE INTERESTED IN THE BIOLOGY, WE USE MODALITY TO DESCRIBE WHAT WE WANT AND BASICALLY THE FACT THAT THESE ARE COMPLIMENTARY FORMS THE BASIS WHY WE NEED MULTI-MODALITY MULTI-FUNCTIONAL AGENTS AS I'LL DISCUSS. FIRST I WANT TO INTRODUCE THE DIFFERENCE BETWEEN CONVENTIONAL TARGETING AND TARGETED DELIVERY. WITH CONVENTIONAL MOLECULAR TARGETING WE HAVE A KINASE INHIBITOR, YOU GIVE TO IT THE PATIENT, IT GOES ALL OVER THE BODY, HITS ALL SORTS OF THINGS, THE TARGET AND EFFECT, IT'S NOT THAT TOXIC SO YOU CAN KEEP GIVING IT NO PROBLEM. IN IMAGING WE'RE STRUGGLING MORE IN TERMS OF DRUG DEVELOPMENT, IN TERMS OF DELIVERING SOMETHING JUST TO A SPECIFIC CELL OR TISSUE AND THEN RIPS AWAY FROM THAT TISSUE. THAT'S WHAT TARGETED DELIVERY IS, TO DO THAT YOU NEED SOMETHING MULTI-FUNCTIONAL ACTIVE AGENT BUT ALSO AFFINITY LIGAND THAT IS GOING TO BE DIFFERENT, IT'S AN ENTITY PART OF THE MOLECULE THAT WILL BE DIFFERENT MECHANISM WE'RE TRYING TO USE IT'S INHERENTLY MULTI-FUNCTIONAL, YOU NEED A FUNCTIONAL AGENT A MULTI-VALENT AGENT IF YOU ATTACK A PERSON LIKE CANCER, IF YOU HAVE ONE TARGET OPT CELL YOUR CANCER IS GOING TO MUTATE, GET AWAY FROM THAT TARGET. IF IT'S ONE AGENT P YOU USE FOR IMAGING ORTHER THERAPY YOU TAKE OUT A COUPLE OF TARGETS AT ONCE MULTI-VIOLENCE OR HETERO BIVALENT COMPOUND THAT BIND TWO TARGETS SO IF YOU LOSE ONE YOU STILL GET IT, OR MULTI-FUNCTIONAL. AND SYNERGY BETWEEN THE MODALITIES SO OPTICAL MR AND PET, WITH OPTICAL TECHNIQUES BEST RESOLUTION CELLULAR, SUBCELLULAR, AND RADIONUCLIDES ARE EASY TO DETECT. THIS IS THE HEART OF DEVELOPING MULTI-MODAL IMAGING AGENTS TO LEVERAGE THE BENEFITS OF EACH INTO A SINGLE AGENT OR USE THEM. ONE AFTER THE OTHER. THERE'S PRECISION PHARMACOKINETICS FOR THERAPY WHERE YOU MIGHT HAVE AN AGENT USED FOR IMAGING SUCH AS OPTICAL IMAGE AND THERAPIES SUCH AS PHOTODYNAMIC THERAPY WHERE YOU KNOW WHERE YOUR THERAPY IS GOING BECAUSE YOU CAN SEE IT AND THEN DIAGNOSTIC AGENTS WE HEARD ABOUT WHICH ARE INLEARNLY MULTI-FUNCTIONAL. THE WAY I DIVIDE THESE UP IN MY MIND, IS ACCORDING TO SIZE, WEIGHT OR LENGTH. LOW MOLECULAR AGENTS LOOSELY DEFINED LESS THAN A THOUSAND GRAMS PER ML, NANOMEDICINES ON ORDER OF 100 NANOMETERS. THE LOW MOLECULAR WEIGHT AGENTS HAVE THESE ATTRIBUTES. CHEMISTRY IS WELL ESTABLISHED. WE CAN USE THE TOOLS AN MEDICINAL CHEM SRI TO MAKE THESE THINGS LIKE DR. MATHIS SHOWED. HE REPURPOSED A DYE NEVER HAD A CHANCE FOR USED IN IMAGING IN THE BRAIN BY MEDICINAL CHEMISTRY. HE USES THE BIG FOUR WAYS TO CHARACTERIZE THINGS MR MASS SPEC, NOBODY USING MR ANY MORE, OR ELEMENTAL ANALYSIS, YOU CAN CHARACTERIZE LIKE IN THE ORGANIC CHEMISTRY LAB. THEY'RE HOMOGENOUS SO WHEN YOU SYNTHESIZE THEM, THEY'RE IDENTICAL SO PEAKS MATCH UP AND THERE'S NO HETEROGENEITY, THEY'RE PENETRANT THROUGH TISSUES AND CELLS BECAUSE THEY'RE SMALL AND OF COURSE THEY HAVE A CLEAR PATH TO CLINIC BECAUSE THIS IS WHAT EVERYTHING USES, LOW O MOLECULAR WEIGHT DRUGS DOSED ORALLY ONCE A DAY, THAT'S WHAT IT'S ABOUT. MORE RECENTLY WE'RE GETTING TO NANOMED SIN MOST INVOLVES LOW MOLECULAR WEIGH AGENTS BECAUSE THESE CARRY MORE INFORMATION, THEY'RE BIGGER WE ZIZANIAS TALK PREVIOUSLY USING NANOPARTICLES IN CREATIVE WAYS, ADVANTAGES INCLUDE HIGH SURFACE TO VOLUME RARE YOU, SO YOU CAN PUT UP A BUNCH OF DIFFERENCE EPITOPES ON THERE. HETERO QUADRIVALENT IF YOU WANT, PUT ALL FOUR MODAL AT THIS ON THESE AND YOU WON'T -- SO THIS GETS AROUND THE HETEROGENEITY MORE EZLY THAN LOW MOLECULAR WEIGH AGENT WITHOUT AS MUCH INFORMATION. THE PLATFORM IS FLEXIBLE IN THAT YOU CAN EXCHANGE RAREIOUS TARGETING OR AFFINITY LIGANDS WITH A NANOPARTICLE. THE USE OF THESE THINGS AS I WILL SHOW IS INCREASE THERAPEUTIC INDEX FOR TOXIC DRUGS, TO DELIVER WHERE YOU NEED THEM. YOU CAN DO THAT WITH NANOMEDICINES, THEY'RE BORN FOR MULTI-TARGETING. FOR REASONS THAT I MENTIONED. BY FUNCTIONALLIZING YOU CAN CHANGE SHAPE. SO YOU CAN HAVE WORMS, TUBES, SPHERES, WHATEVER. SO YOU CAN TUNE PHARMACOKINETICS AND THAT'S WHY THESE BECOME QUITE USEFUL. SO WHEN YOU'RE DESIGNING MULTI-FUNCTIONAL AGENTS, IS IT INCREASED COMPLEXITY? SO TARGETING LOW MOLECULAR WEIGHT AGENTS PRIMARILY INCREASED COMPLEXITY. THE HIGHER MOLECULAR WEIGHT, YOU HAVE TO USE LINKERS, THE PHARMACOKINETICS ARE LESS PREDICTABLE. BUT FOR NANOMEDICINE, A WHOLE 'NOTHER KETTLE OF FISH, IT'S INCREASED SCIENCE OF TRYING TO FUNCTIONALLIZE THOSE. SO IT IS AN EXERCISE IN MULTI-VALENCY WHERE YOU NEED SOMETHING TO EXPRESS TWO DIFFERENT ADVISIAL SPECIES FOR TWO DIFFERENT MODALITY THES. OR MAYBE ONE IMAGING ASPECT AND TARGETING OR THERAPEUTIC ASPECT. , SO IT'S MULTI-NOT JUST ONE CURRENT OR SEQUENTIAL IMAGING. >> WHEN WE TALK PET MR WE TALK ABOUT DOING A PET SCAN WITH A TYPICAL PAGE AND OVERLAYING WITH A GENERALLY STANDARD ANATOMIC MR. YOU CAN'T DO MR WITH A PET AGENT BECAUSE IT'S ABOUT A 10 MILLION FOLD DIFFERENT CONCENTRATION OF YOUR ABILITY TO DETECT T. SUB-NANOMOLAR VERSUS HALF MILLIMOLAR FOR PET VERSUS MR. IF YOU HAVE A PET AND MR AGENT AND IF YOU WANT TO MAKE IT A VERY LOW SPECIFIC ACTIVITY, THEN YOU MIGHT BE ABLE TO SEE IT ON THE EMR OR PET SCAN BUT WE DON'T LIKE LOW SPECIFIC ACTIVITY ON PET SCANS. THEN OF COURSE PHARMACO KIP TICK KS, VERY IMPORTANT -- CONSIDERINGS VERY IMPORTANT FOR WEIGHT OR NANOMEDICINE T. WAY YOU MAKE THESE IS GOING TO BE WE'LL DISCUSS IN A MINUTE. WHEN YOU MAKE THE NANOMEDICINES YOU CAP ALL PREDICT HOW MANY EPITOPES ARE GOING TO BE FUNCTIONALLIZED OPT SURFACE. IT'S A STATISTICAL DISTRIBUTION. SO YOU DON'T HAVE A UNIFORM PARTICLE, THE PHARMACOKINETICS ARE TRICKY. MOLECULAR GENETIC REPORTER SYSTEMS LEND THEMSELVES TO MULTI-MODEAL AND FUNCTIONAL APPLICATIONS AND THEY GET MORE COMPLEX AS THEY ADD MODALITIES. ELEMENTS OF MULTI-FUNCTIONAL AGENT, THE BUSINESS, IMPORTANT PART IS HERE U IS IN MY MIND AFFINITY AGENT. THAT'S GENERALLY ANTIBODY PEPTIDE OR SMALL MOLECULE, IN RECENT YEARS, THERE HAS BEEN A COTTAGE INDUSTRY IN USING PHASE DISPLAY TO GENERATE ANTIBODIES AN PEPTIDES FOR VARIOUS TARGETS. YOU CAN USE DIRECTED EVOLUTION FOR APT HERS SO THIS IS NO LONGER SUCH A BOTTLENECK AS IT USED TO BE. YOU WOULD HAVE TO GET LUCKY AND FIND AFFINITY AGENT BUT NOW YOU CAN GENERATE THOSE. THEN YOU HAVE PHARMACOKINETIC MODIFIER WHICH IS A LINKER THAT LINKS THE AFFINITY AGENT OVER TO THE THING THAT MAKES THE THING VISIBLE. THIS CAN ALSO BE USED TO INCREASE VALENT CITY BY FUNCTIONALLIZING MR GROUPS OR MODALITIES THERE. THIS ENABLES IMAGING FROM DIFFERENT MODALITIES. THIS IS A SPECIFIC EXAMPLE BILL OF AGENT LIKE THIS, THE LINKER AND YOU HAD RINIEM 188 FOR THERAPY, THIS IS GOING TO BE FLUORESCENT BECAUSE OF THE BIS QUINN LYNNE AND IF YOU HAVE (INAUDIBLE) YOU CAN YOU CAN IT FOR IMAGING, OPTICAL RADIO THERAPEUTIC AND YOU CAN FOLLOW IT IN CELLS. SO THAT'S MULTI-FUNCTIONAL AGENT LOOKS LIKE. THE PRACTICAL EXAMPLE WHY YOU WOULD WANT TO DO THIS IS SHOWN HERE. HERE IS AN AGENT RADIO ACTIVE AS WELL AS OPTICAL. NEAR INFRARED DYE. YOU MIGHT USE THIS, GIVE IT TO A PATIENT ON DAY 1 AND YOU CAN PERFORM YOUR SPECK SCAN FIND OUT WHERE THE TUMOR IS, TUMOR TARGETING AGENT AND LOUT ANOTHER INJECTION BECAUSE APT L CALTECH NEBBINGS ARE SENSITIVE. THIS IS NANOMOLE TRACER DOSE, YOU CAN A DAY LATER TAKE A LOOK USING NEUROINFRARED IMAGING TO SEE WHERE YOU ARE ON OPTICAL IMAGE. SO DAY ONE, STAGING, IF TUMOR IS WHERE YOU WANT IT TO BE YOU CAN GET UP CLOSE AND PERSONAL WITH -- WHICH IS WHAT YOU NEED TO DO WITH FIBER OPTICS FOR EXAMPLE. AND USE THIS FOR INTEROPERATIVE GUIDANCE. STAGING AN SURGICAL GUIDANCE. THIS IS A LITTLE COMPLICATE BUD IF YOU JUST KIND OF LOOK AT THESE BLUE IMAGES DOWN HERE, ON THE LEFT THESE ARE FOUR MICE THAT WERE OPERATED UPON WITH THE NEAR INFRARED GUIDANCE, THEY HAVE GOT THE PROBE. THESE ARE FOUR MICE THAT DIDN'T GET THE IMAGING AGENT OR THE PROBE. IF U YOU WAIT A WEEK AFTER SURGERY A LITTLE TUMOR COMES BACK WHICH MEANS IF YOU CAN USE THE DYE TO START WITH YOU CAN GET THE ENTIRE TUMOR OUT. EVERY CELL, MARGIN IS NEGATIVE. THAT IS WHY HAVE A MULTI-MODALITY IMAGING AGENT. THE OTHER THING YOU CAN DO, IF YOU HAVE ONE BOTH OPTICAL AS WELL AS RADIO ACTIVE, YOU MIGHT BE ABLE TO LOOK AND WATCH, USE THE OPTICAL ASPECT FROM RECEPTORS COME TO CELL SURFACE AND SEE WHERE THEY GO. FOR THESE AGENERALS THEY GO IN HERE FOR THE CENTER CELL AND YOU THINK WOW THAT'S GOOD. THEY GET HEAVILY CONCENTRATED THERE. SO THIS PROVIDES THE RATIONALE FOR A RADIO THERAPEUTIC AGENT, OJ ELECTRON EMITTER WHERE YOU HAVE TO BE RIGHT UP AGAINST THE DNA TO USE IT. AND WE HAVE DONE THAT, WE HAVE LABELED SUCH AN AGENT, WITH I-125. YOU CAN SEE THESE MICE TEND TO SURVIVE VERY WELL. THIS PROVIDES RATIONALE TO USE THE THERAPEUTIC AGENT WITH BOTH MODALITIES. GOAL BEG DEVICE ENABLESIOUS TO DELIVER SI RNA IN THIS CASE AGAINST COLON KINASE AS WELL AS ENZYME DEAMINASE, YOU CAN RADIO LABEL IT AND PUT GAD LIP YUM ON IT AND YOU CAN SEE HERE AS YOU INJECTION THIS BECAUSE THERE ARE AFFINITY AGENTS, IT WILL BIND TO THE TARGETED TOO MORE BETTER THAN TO THE TUMOR THAT DOESN'T EXPREGNANT TARGET THOUGH THERE'S EPR THERE. YOU CAN ALSO USE NMR TO SHOW DECREASE IN T-1 THOUGH IMAGING ARE NOT BREATHTAKING, BUT THERE IS A DIFFERENCE THERE. BUT YOU CAN USE MR SPECTROSCOPY TO WATCH HOW SI RNA IS WORKING. SO CHOLINE KINASE SI RNA IS TURNING OFF THE PRODUCTION OF CHOLINE AND SPECTROSCOPY CAN BE USED TO SHOW THAT. AND THE BACTERIAL DEAMINASE IS USED BY FIVE FLOURALCYTE SCENE OVER TIME CONVERTING TO FIVE FLOUR URACIL, AND THAT'S IMPORTANT BECAUSE 5 FU WORKS GREAT BUT IT'S TOXIC, THE WHOLE PURPOSE IN MY OPINION FRANKLY OF NANOMEDICINE LIKE THIS, IS TO GET CONTROL. OVER WHERE YOU'RE PUTTING THINGS. HERE YOU PUT THEM RIGHT WHERE THE TUMOR IS. SO THEY AREN'T SO TOXIC SO FROM NANOPLEX TO NANOPARTICLE, THIS IS A PARTICLE THAT WE CAN PUT SOME DRUG DOSE TACK SILL SOMETHING HIKE THAT INSIDE AND WE CAN DECRATE THE OUTSIDE WITH AFFINITY AGENTS, WE PICKED IN THIS CASE ONCE AGAIN THESE UREAS WHICH WILL BIND TO PSMA. AND WE CAN ACTUALLY MAKE SURE THE UREAS ARE OPT OUTSIDE, THERE'S CARBOXYLATES HERE. ON THE INSIDE THERE'S A DYE. WE CAN SHOW THAT IN VITRO THAT THE UNTARGETTED -- I'M SORRY, THE TARGETED PARTICLES BIND BETTER THAN UNTARGETTED PARTICLES IN VITRO. IN VITRO IS ALWAYS EASY, THAT'S AS FAR AS WE TOOK IT. WE ALSO DID A THERAPEUTIC STUDY. THIS SHOWS BASICALLY THIS IDEA OF CONTROL WHERE WE HAVE DOSE TACK SILL, NON-TARGETED PARTICLES AND WE HAVE THE TARGETED PARTICLES. AND IF WE BATHE THESE CELLS IN VITRO FOR 20 MINUTES, WITH THESE DIFFERENT AGENTS WE'LL SEE THE CONTROL CELLS THEN RINSE AWAY AFTER 20 MINUTES OF BATHING, WE'LL SEE THE CONTROL CELLS WILL GROW, THE DOE IS A TACK SILL CELLS WILL DYE, THE NON-TARGETED NANOPARTICLES WILL KIND OF DYE AND THE TARGETED ONES ARE AS FOOD AS DOSE TACK SILL. IF YOU WAIT 96 HOURS OF YOU RINSE THE AGENTS YOU GET AN EXAGGERATED EFFECT. THE POINT HERE, IS THAT THE TARGETED PARTICLES WORK AS WELL AS THE DOSE TACK SILL DOES. THE DIFFERENCE IS THAT THIS GOING TO BE ONLY WHERE TUMOR IS, NOT ALL OVER THE BODY. SO A COMPANY BIND BIOSCIENCES, THIS IS HOW YOU TRANS LATE THESE, YOU HAVE TO -- THE PLANETS HAVE TO ALIGN SO SOME COMPANY ACTUALLY IS DOING EXACTLY WHAT YOU HAPPEN TO BE WORKING ON, THEY LICENSE OUR PATENT FOR THIS, THEY PUT IT IN PATIENTS. SO THEY SHOW IN THIS PATIENT WITH METASTATIC CARCINOMA, IT IS A TARGETED TARGETEDS TO TACK SILICON TANNING PARTICLE, THAT TOOK OUT METASTASIS, THE ISSUE HERE IS THAT THIS IS A MULTI-FUNCTIONAL AGENT IN THE SENSE IT'S DELIVERING A DRUG AND IT HAS APPROXIMATE AFFINITY TO IT. SO THIS ISN'T EPR EFFECT. IF YOU WANT TO MAKE IT INTO (INDISCERNIBLE) YOU HAVE TO FUNCTIONALLIZE THESE THINGS. IN THE OLD DAYS, WHEN I WAS LEARNING IMAGING WITH PET, YOU HAD TO BE A CHEMIST TO DO THIS. NOW THERE'S SO MANY PROSTHETIC GROUPS, ACTIVE ESTERS AND ALPHA HELO KETONES AND MOST RECENTLY, THEY HAVE CLICK CHEMISTRY TO ENABLE YOU TO LABEL SMALL MOLECULES, NANOPLEXES OR NANOPARTICLES, THEY CALL IT CLICK CHEMISTRY BUT ANYONE THAT'S A CHEMIST KNOW THERE'S NO SUCH THING AS CLICK ANYTHING. THAT WORKS NOT QUITE THAT EASY BUT EASIER THAN OLDER TECHNIQUES. SO YOU CAN ACTUALLY TAKE AN AGENT LIKE THIS AND PUT YOUR RADIO ACTIVE MOIETY IN THE KEY LATER AND YOU CAN IN A WAY CLICK IT UP TO A NANOPARTICLE THAT HAS SIDES ON THE SURFACE BUT P OPTIMIZATION TO THIS STAGE, I DONE SHOW IT BUT THERE'S PROTECTION, DEPROTECTION STEPS SO IT'S NOT JUST STRICTLY A CLICK. YOU CAN MAKE A AGENT WITH WITH A TARGETED NANOPARTICLE THAT CONTAINS A DRUG AND ALSO CAN BE USED TO VISUALIZE I SHOW THIS BECAUSE HERE IS THE TARGETED PARTICLE, HERE IS NON-TARGETED PARTICLE. THIS IS THE TUMOR EXPRESSES THE TARGET, THIS DOES NOT. YOU SEE THE TARGETED PARTICLE GETS IN HERE BECAUSE OF EPR WHICH YOU GET. IF THE TUMORS GET BIGGER WE FIND THE PARTICLES DON'T GET IN THERE THAT GREAT. IF YOU CUT TUMORS ON A IMAM MA COUNTER YOU SEE MORE UPTAKE FROM THE TARGETED VERSUS THE NON-TARGETED BUT YOU TEND TO GET A DRASTICALLY THERAPEUTIC EFFECT FROM TARGETED VERSUS NON-TARGETED WHICH I'M STILL UNABLE TO EXPLAIN. SO TARGETING HELPS IS THE TAKE HOME MESSAGE. SO THE LAST COUPLE OF THINGS TO MENTION, TALK ABOUT HOW MOLECULAR GENERAL IT CAN IMAGING LENDS ITSELF TO THIS MULTI-MODEAL MUNG FUNCTIONAL APPROACH. IF YOU HAVE A GENE OF INTEREST, HERE YOUR FAVORITE PROMOTER YOU CAN'T SEE IT DIRECTLY SO YOU HAVE THE LINK ITS ACTIVITY TO REPORTER YOU CAN SEE LIKE BETA GALACASITASE, LUCIFERASE GFP USING EXTERNAL GAM MANY CAMERA, YOU CAN USE REPORTER GENES SUCH AS HSCTK THAT PRODUCES A PROTEIN YOU CAN IMAGE WITH IN THIS CASE SPECK. SO INDIRECT READ OUT FROM YOUR GENE OF INTEREST UPON ACTIVATION BECAUSE YOU CAN SEE THE REPORTER GENE. SO A GUY NAMED PAUL SHUSHER I WAS AT A MEETING WITH HIM IN '04 AND HE SHOWED ME THIS SLIDE WHERE HE BASICALLY HAS THEE KINDS OF MAMMARY CELLS, NON-MALIGNANT EPITHELIAL CELLS AN THESE ARE CANCER MCS-7 CANCER CELLS. A GREEN FLUORESCENT PROOFING UNDER CONTROL OF CMV PROMOTER, IT IS ALWAYS ON SO IF YOU HAVE GOT NON-MALIGNANT CELLS THEY'RE GROWN BECAUSE THIS IS ALWAYS ON. IF YOU HAVE MALIGNANT CELLS THEY'RE GREEN. BUT YOU HAVE THIS PROMOTER PROGRESSION ELEVATION 3 GENE PROMOTE ONLY ACTIVE IN THE PRESENCE OF CANCER BECAUSE THERE ARE TRANSCRIPTION FACTORS IN THE CANCER, NOT INNAMATION, PHOTONOT PRE-MALIGNANT CONDITIONS BUT CANCER TO TURN THAT ON SO HUMAN EPITHELIAL CELLS TRANSFECTED WITH WITH THE PEG DRIVEN GFP WILL NOT TURN ON WHEREAS CANCER CELLS DO. SO THIS WOULD BE A NICE THING TO TRY IN VIVO. WE CLONED PEG PROMOTER IN LIEU RECEIVE RACE AS WELL AS HSVTK, BIOLUMINESCENCE IMAGING AND SPECK TO SEE THESE METASTASIS, THIS IS METASTATIC MELANOMA BUT IT WORKS FOR ANY CANCER, WE TRIED MELANOMA, PANCREATIC, PROSTATE, TRIP NEGATIVE BREAST CANCER AND IT SEEMS TO WORK. THE WAY IT WORKS, THIS IS DELIVERED INTRAVENOUSLY WITH POLYETHYLENE NANOPARTICLE ALL OVER THE BODY BUT THE REPORTERS ONLY TURN ON WHEN THEY CONTACT CANCER THEN COME IN WITH YOUR IMAGING AGENT AND IMAGE WHERE THE MA TASTASIS ARE. WHAT IS NICE ABOUT THIS, WE SAW A TALK EARLIER ABOUT BROWN FAT, FDG, IN THE CHEST TAKEN BY BROWN FAT BY THE HEART BUT THIS TECHNIQUE, THE REASON I SHOW THIS, I WANT TO SHOW NANOPARTICLES GIVE GOOD SIGNAL TO NOISE IF YOU'RE PATIENT AND WAIT TO RINSE FROM NON-TARGET SITES. YOU CAN SEE LITTLE TUMORS, YOU CAN SEE BIG TUMORS IN THE CHEST BECAUSE THERE IS NO UPTAKE IN THE HEART BECAUSE IT E NOT MALIGNANT TISSUE. SO THE NEXT THING YOU CAN DO IS MAKE THIS INTHE AN AGENT USING MAYBE I-131 LABELED FIU INSTEAD OF I-125 AND WE GET A MODEST BENEFIT HERE IN THIS VERY PRELIMINARY STUDY SO YOU CAN USE THAT AS A AGENT. RELATED TO THIS IS BRINGING IN ANOTHER MODALITY SO OPTICAL AND NUCLEAR. HOPE THAT WORKS. THAT'S A VERY KNIGHT NICE MOVIE THAT EXPLAINS CHEMICAL EXCHANGE SATURATION TRANSFER. THIS IS AN NMR TECHNIQUE, DR. MEADE SHOWED EARLIER THEY'RE DESPERATE TO GET SENSITIVITY OUT OF THEIR MODALITY AND TRY TO DO MOLECULAR IMAGEING WITH IT YOU HAVE A SPECIES WITH AMID PROTONS IN A PROTEIN OR TUMOR, THEY EXCHAIN WITH WATER PROTONS THE IF YOU IRRADIATE THAT AMIID FREQUENCY YOU GET AN EFFECT ON THE WATER PROTON AS YOU CAN SEE HERE, THIS PEAK SHRINKS DOWN AND IT'S THE WATER THAT YOU'RE MEASURING WITH NMR SO YOU GET INDIRECT READ OUT ON WHAT'S GOING ON OVER HERE. WITH AMID PROTONS, AMED PROTEINS, IT'S CLEVER TECHNIQUE THAT BOB DEVELOPED IF YOU USE PEG PROMOTER TO DRIVE PROTEIN WITH LOTS OF LICENSE WITH AMID PROTONS, THIS IS A RAT GLIOMA, IF YOU HAVE THE LYSINE RICH PROTEIN DRIVEN BY CMV PROMOTER YOU CAN SEE YOU CAN USE THAT TO SEE THAT. PEG PROMOTER FOR PROMOTER THAT'S GOING TO TURN ON IN CANCER AND THAT WAS ASSESSED ALSO. THIS GIVE AS TRIPLE MODALITY, WHERE WE CAN USE RADIO PHARMACEUTICALS OR OPTICAL LUCIFERASE OR LYSINE RICH PROTEIN SO WE CAN USE THESE MODALITIES TO LOOK AT ANY CANCER BECAUSE YOU HAVE TO HAVE CANCER TO ACTIVATE PROMOTERS SO THAT'S THE NEXT STEP. THE LAST THING I WANT TO SHOW THIS IS CLEVER. MULTI-MODALITY PROBES BUT PETER CARAVAN'S GROUP HAS A NICE APPROACH SO THEY DO THIS WELL. YOU CAN SEE THIS IS A PROBE FOR FIBRIN. THIS IS BASICALLY BOUND TO BUY THIS PEPTIDE AND YOU CAN SEE YOU'RE ABLE TO SEE ON MR FIBRIN OPPOSED TO FIBRINGEN OPTICAL IMAGING SAME THING AND PET AS WELL. HOW DO YOU MAKE A PROBE LIKE THIS? A COMBINATION OF SOLID PHASE AND SOLUTION PHASE SYNTHESIS, THEY FUNCTIONALLIZE THE END TERMINAL PORTION WITH FLUROPHORE, KNOWING THAT THE ORGANIC FLUROPHORE WILL MESS UP PHARMACOKINETICS BECAUSE THEY'RE LIPOPHYLIC, KELATOR IS ON THE OTHER SIDE, BUT HE CLEAVED IT FROM THE RESIN CYCLIZES THE PEPTIDE AND PUT THE DOTA OVER HERE. SO ORGANIC FLUROPHORE AND DOTA AND THAT CAN BIND COPPER 64 OR CAN BIND GADOLINIUM. VERY CAREFUL TO OPTIMIZE, THESE TWO DIFFERENT PARTS OF THE MOLECULE. SO THAT YOU STILL RETAIN THE AFFINITY FOR FIBRIN, THIS IS A BEAUTIFUL EXAMPLE OF VERY CAREFUL OPTIMIZATION WHICH ALL THESE MUNGSAL AGENTS REQUIRE. THIS IS A AN EXAMPLE OF HOW WE HAVE TO START THINKING ABOUT SPECK MR PROBES. DR. CHOW A COLLEAGUE CURRENT SPECK AND MR IMAGING AND AGAIN THIS IS FUNCTIONAL, I SHOULD SAY -- THIS IS SUPER IMPOSED STANDARD SPECK AGENT. BUT THERE'S OPPORTUNITY IN THIS AREA. I THINK BY LEVERAGING THESE DIFFERENT MODALITIES WITH EACH OTHER THEY COULD BE SI ANYWHERE JUSTIC AND GET AROUND HETEROGENEITY, THEIR BE FAIRNOSTIC, IT'S NOT EASY TO DO BUT REPRESENTS THE FUTURE. OF WHAT WE HOPE TO DO WITH MOLECULAR IMAGING. THESE ARE PEOPLE, CHIEF CHEMIST RON AND OTHERS THAT WORKED ON THIS, OUR COLLABORATORS AND THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> I WOULD LIKE TO ASK ALL SPEAKERS FROM THIS MORNING SESSION TO COME UP, WE IS CAN HAVE A PANEL DISCUSSION FOR ABOUT 25 MINUTES. I (INAUDIBLE) 25 QUESTIONS SO HOPEFULLY THE AUDIENCE HAS OTHER QUESTIONS OTHERWISE YOU WILL GET BOARD WITH MINE. -- BORED WITH MINE. PEOPLE WATCHING VIA VIDEOCAST CAN ALSO SEND IN QUESTIONS. THE EMAIL ADDRESS IS NIBIB UNDERSCORE MY WORKSHOP 2013@MAIL.NIH.GOV. FROM WOULD ANYONE LIKE TO TAKE THE FIRST QUESTION? MAYBE I CAN START ONE OF MINE. A NUMBER OF PEOPLE BROUGHT UP FIBROSIS AND INFLAMMATION. PART OF FTG IS VERY SUCCESSFUL L IN PART BECAUSE IN MANY SITUATIONS ARE THESE GENERAL USE GOING TO WIN IN THE END BECAUSE OF CLINICAL USE -- IT WILL BE A WIDER SPREAD USE IN THE CLINIC, OR IS THERE REALLY GOING TO BE A PUSH TOWARDS MORE SPECIFIC CASES DESPITE QUESTIONS OF HETEROGENEITY WHICH PEOPLE HAD QUESTIONS FOR AS WELL? >> I THINK THAT BOTH OF US MIGHT BE ABLE TO ADDRESS THAT. I THINK THE GENERAL ONE LIKE (INAUDIBLE) THAT I SHOWED, ARE EXTREMELY USEFUL CLINICALLY. ABSOLUTELY. A LOT OF PEOPLE THAT I WORK WITH AT THE NIDDK WHO FOCUS ON LIVER FIND THEM TOO NON-SPECK FOR CLINICAL RESEARCH, THAT'S FOR SURE. ON THE OTHER HAND, WE WOULD -- TELL ME NOW HOW WELL DISEASE PROGRESSES AS A FUNCTION OF THE LOAD OF COLLAGEN, FOR INSTANCE? WE WEAPON KNOW THE ANSWER TO YOUR QUESTION IN TERMS OF LIVER DISEASE ANYWAY. >> I GUESS I DIDN'T FULLY UNDERSTAND YOUR QUESTION. WERE YOU ASKING TECHNIQUE OR AGENT THAT COULD IMAGE FIBROSIS ACROSS ORGAN SYSTEMS? >> IF SO, IS THAT DESIRABLE? SIMILARLY FOR INFLAMMATION? >> I CAN'T ANSWER THAT. THE MYOFIBROBLAST THAT I WAS FOCUSING ON. I DON'T REALLY UNDERSTAND ANY DIFFERENCES I DON'T KNOW IN THE BIOLOGY PANE BETWEEN THAT PARTICULAR CELL -- BETWEEN THAT PARTICULAR CELL WITH CELLS IN THE HEART AND HAVE SIMILAR FUNCTIONS IN OTHER ORGANS. FOR THE HEART, CERTAINLY, THE AGENTS THAT HAVE BEEN TRIED TO DATE HAVE LIMITATIONS SIMPLY BECAUSE THERE ARE DRUGS THAT ARE CURRENTLY USED IN HEART FAILURE, MANY PATIENTS ARE ON THEM. IT WOULD MEAN STOPPING THE DRUGS. OR WONDERING HOW LONG IT WILL TAKE BEFORE YOU STOP A DRUG BEFORE YOU IMAGE YOUR TARGET. ALPHA 3 BETA 3, ONE OF THE TARGETS, IS NOT SPECIFIC ENOUGH I DON'T THINK. WHILE EXPRESSED ON THE MYOFIBROBLASTSTHEY EAR EXPRESSED ON OTHER CELLS TOO. BUT I THINK THIS IS AN AREA LOOKING FOR UNMET NEED, TO GET SOME SMART PEOPLE OUT THERE TO WORK ON THIS PARTICULAR AREA. >> ANYONE LIKE TO ASK SOME QUESTIONS? (OFF MIC) >> BECAUSE COMPLEXITY AN MATERIALS YOU HAVE TO USE IT TO SYNTHESIZE COMPOUND, MUCH MORE BETTER IMAGING AGENT, WHAT DO YOU THINK ABOUT THEM -- >> I DON'T THINK THOSE ARE GOING TO BE TRANSLATED TO THE CLINIC. THANK YOU. ACTUALLY, MAYBE EVENTUALLY BUT IN MY LIMITED EXPERIENCE TRYING TO GET THINGS TO THE CLINIC, IT'S ALL ABOUT HAVING THINGS IN KID FORMULATIONS THAT YOU DON'T USE HIGH PERFORMANCE LIPOCHROMATOGRAPHY, ET CETERA. SO IF YOU HAVE THAT FIBRIN AGENT WILL BE USEFUL IN IF YOU ARE MOTIVATED TO DO IT AND YOU HAVE A SHAKE AND BAKE WAY TO HAVE IT MADE AND CONVINCE A DONOR, YOU MIGHT BE ABLE TO GET TOTE THAT POINT BUT LOOKING HISTORICALLY THERE AREN'T A LOT OF THINGS THAT ARE REIMBURSED BY CMS. THAT'S KIND OF AS DR. MEADE CAN TELL YOU WHERE YOU GET COMPANIES INTERESTED TO TRANSLATE THINGS. IN THE WORLD OF THESE VERY SUCCESSFUL AMYLOID IMAGING AGENTS, THERE'S MAYBE ONE NOW THAT'S BARELY APPROVED WITH TREMENDOUS EFFORT SO A MAJOR CHALLENGE. BUT IF YOU'RE MOTIVATED AND YOU HAVE INDICATION FOR IT, IT'S POSSIBLE BUT IT'S JUST POSSIBLE, NOT PROBABLY. >> DO YOU THINK IT'S IMPORTANT TO THINK WHETHER PROBES ARE USED IN BIODISCOVERY PHASE OR MAKE IT THROUGH TO CLINICAL TRANSLATION? DOES THAT ENTER YOUR MIND? >> ONE LITTLE FOLLOW-UP TO THAT VERY NEGATIVE COMMENT THAT I MADE. IF UP THINGS TO GO BENEATH HUMAN SKIN WHERE YOU HAVE TO DO TOXICITY STUDIES AND GMP SYNTHESIS, THERE'S A SERIES OF DIAGNOSTICS DEVELOPED THAT YOU DON'T HAVE TO GIVE TO PEOPLE THAT YOU CAN USE OUTSIDE THE BODY, MIX WITH BLOOD, ET CETERA. SO THERE'S POSSIBILITY. THAT'S JUST AS VALID CLINICAL TRANSLATION. LOOKING AT THE PATHOLOGY SPECIMENS EVEN. BUT IF YOU PUT IT BENEATH HUMAN SKIN THAT'S WHERE THE REAL CHALLENGE COMES IN. >> COUPLE OF SPEAKERS DISCUSS, LOVED YOUR IMMANNING PROBES FOR NEUROINFLAMMATION. WOULD ANY SPEAKERS CARE TO ADDRESS MOLECULAR IMAGING PROBES FOR INFLAMMATION BELOW THE FRAME AN MAGNUM AND SPECIFICALLY DIFFERENTIATING BETWEEN THE INFLAMMATORY PROCESS AND ANY UNDERLYING INFECTIOUS DISEASE PROCESS CAUSING THE INFLAMMATION FROM? >> I WILL TAKE A STAB AT IT. SUCH WOULD BE USEFUL, THEY DON'T EXIST, THERE IS A NEED FOR THEM. I'M FOCUSED ON NEUROINFRAMATION BUT PERIPHERAL INFECTIONS INFLAMMATION MAKE SENSE, IT IS TOUGH GOING SO WE NEED TARGETS AN PROBES FOR THE TARGETS. THERE'S WORK IN THAT AREA BUT TO DATE THERE'S NO SUCCESSFUL AGENT. >> WE HAVE BEEN LOOKING (INAUDIBLE) AND EXPRESSED IN MICROFLESHINGS IN VIVO AND BRAIN AND IN MI MAYBE THAT'S ONE DIRECTION, BECAUSE OF THE (INDISCERNIBLE) SCIENTIFIC COMMUNITY FROM PURSUING THIS RESEARCH OR DEVELOPMENT. >> DID YOU WAN ME TO RESPOND TO THAT? >> BRAINSTORM. >> I'LL PASS IT TO OUR ACCOMPLISHED PANEL HERE, I THINK THEY HAVE MORE DETAIL ANSWERS THAN I CAN GIVE. COULD YOU REPEAT THE QUESTION? >> THE PROBE FOR MI ARE THERE FOR MICROGLIA ACTIVATION. (INDISCERNIBLE) ABOUT SEVEN PAPERS NOW BUT I THINK MAYBE IN CONFLICT OF INTEREST BECAUSE (INAUDIBLE) IS ONE OF THE CO-AUTHORS SO (INAUDIBLE) THE REASON, QUESTION I ASK, PEOPLE SHYING AWAY FROM GENOMIC INFLAMMATION COGNITIVE IMAGING AND CURBLY LIKE DR. MEADE SAID, THERE ARE BLOCKING FDA APPROVE EITHER (INDISCERNIBLE) BECAUSE OF THE TOXICITY PREVENTING US FROM CONTRAST AGENT OR TARGETING IMAGING. >> THE GAD COMPOUNDS AREN'T TOXIC, THE IRON WAS TAKEN OFF RECENTLY. I THINK THE BIGGER PROBLEM, WILL IT BE REIMBURSABLE? I THINK IF YOU TALK TO ANY FRONT LINE RADIOLOGIST THEY CAN TELL YOU IN THE LAST FIVE YEARS MORE RADIO LOGICAL TECHNIQUES ROUTINELY USED FIVE YEARS AGO ARE BEING CUT. IF THAT'S THE CASE, A COMPANY LOOKING FORWARD TO SAYING YES, I MIGHT ADD A PREMIUM TO YOUR DIAGNOSTIC TO DIFFERENTIATE BETWEEN THIS OR THAT, IT WILL NEVER MAKE IT BECAUSE IT'S NOT REIMBURSABLE. THAT'S NOT FROM A SAFETY OR TOXICITY PICK OF VIEW, JUST THE WILL POWER TO SAY YES, THERE IS A PREMIUM FOR SAYING TO SOMEBODY 20 YEARS BEFORE ONSET OF ALZHEIMER'S OR CANCER THAT WE'RE GOING TO SAVE MONEY BUT NOBODY WILL AT IT THAT WAY. AT LEAST FROM MY POINT OF VIEW. >> QUESTION. IN THE BACK. (OFF MIC) >> NOT CYNICAL, I AGREE WITH IT. I WOULD LIKE TO HEAR FROM OTHER FOLKS BUT WHEN YOU START ADDING THERAPEUTIC THE PHARMA FOLKS GET FAIRED UP SO MANY HAVE BEEN WORKING ON FOR YEARS IS A FUTURE. >> ALTHOUGH CONVERSELY I THINK AREAS WHERE WE HAVE NO EFFECTIVE THERAPY IF IT CAN BE ARGUED THE LACK OF THERAPEUTIC APPROACH IS BECAUSE OF INABILITY TO FIND POPULATION THAT YOU'RE LOOKING FOR THEN THE ENDOPHENOTYPE FROM IMAGING OR ANYTHING ELSE YOU CAN COME UP WITH WITH IS CRITICAL TO MOVING FORWARD AND THERE ARE A NUMBER OF CONDITIONS LIKE THAT. >> I HAVE A QUESTION ABOUT CXCR4 RECEPTOR. AND I BELIEVE STILL KNOW THEIR LOCATION OF THIS RECEPTOR, THERE IS SOME BIOLOGICAL -- ACTUALLY I COULD SEE IN ONE STUDY I CAN SEE HOW THE RECEPTOR IS GOING OUT OF THE NUCLEUS TO THE CYTOPLASM AND THE QUESTION IS, IF THAT IS POSSIBLE -- THIS COULD MAYBE ADD SOMETHING BECAUSE STILL I THINK THAT THIS RECEPTOR SENSITIVITY OF THIS IMAGE IS NOT ENOUGH. IT WOULD BE POSSIBLE TO HAVE METHOD TO SEE TO -- INSIDE THE CELL TO VISUALIZE ALSO THIS INTRANUCLEAR RECEPTOR. >> I GUESS I HAVE TO ANSWER THAT QUESTION. I'M NOT -- LET ME START BY SAYING, THESE RECEPTORS AS FAR AS I KNOW HAVE KNOW THEY'RE NOT LOCATE IN THE THE NUCLEOIUS. THEY HAVE NO NUCLEAR ROLE. THE RECEPTOR EXISTS ON SURFACE OF CELL AFTER BINDS LIGAND AT SOME LEVEL CONSTITUTIVELY, IT'S INTERNALIZED, PROPORTION OF RECEPTORS DEGRADED, PROPORTION IS RETURND TO THE SUR A FAST OF THE CELL AND -- SURFACE OF THE CELL. IN THE KISS OF CXCR4 THERE'S EVIDENCE OF INTRACELLULAR COMPARTMENTS FROM WHERE RECEPTOR IS STORED IN THE SENSE MOBILIZED TO THE CELL SURFACE. I DON'T KNOW OF ANY FUNCTION EXCEPT SURFACE RECEPTOR. I CERTAINLY DON'T KNOW ANY AGENT THAT WERE PENETRATE CELL MEMBRANE AND VISUALIZE RECEPTOR INTRACELLULARLY. NOT SURE I ANSWERED YOUR QUESTION. >> I THINK THAT VISUALIZING THE ENTER CELLULAR PORTION OF THE RECEPTOR COULD ADD SENSITIVITY AND ALSO -- BECAUSE IF YOU DO IMMUNOSTAINING YOU VERY FREQUENTLY SEE IF -- EVEN THOUGH THAT'S NO NUCLEAR THERE'S CYTOPLASMIC RECEPTORS. ACTUALLY, THERE IS NOT MUCH ON THE SURFACE, I THINK THAT THIS IS TRAFFICKING. IF YOU ONLY WOULD LIKE TO SEE THE EXTERNAL PART OF THE RECEPTOR WHICH IS ON THE MEMBRANE, YOU LOSE SENSITIVITY. >> I CAN ARGUE WITH THAT, IF YOU USE THE DRUG TO TARGET RECEPTOR, YOU'RE INTERESTED IN THE SURFACE RECEPTOR. THAT'S THE PART THAT FUNCTIONALLY IS BIOLOGICALLY OF INTEREST, EXPRESSION OF THE CELL WHICH IS VISUALIZING INTRACELLULAR RECEPTOR, THE DRUG DISCUSSED OREGON ANTAGONISTS -- OR OTHER ANTAGONISTS ARE GOING TO ACCESS RECEPTOR EXPRESSED ON THE SURFACE OF THE CELL, LIKE NATURAL LIGAND. >> WE HAVE A QUESTION FROM THE INTERNET. >> COUPLE OF QUESTIONS FROM VIEWERS VIEWING VIA WEBCAST, THE FIRST ONE IS, REGARDING THE MULTI-MODALITY AGENTS FOR PMR WHAT IS THE ADDED CLINICAL VALUE OF COMBINED AGENT VERSUS WHAT IS CURRENTLY DONE IN CLINICAL RESEARCH, THE USE OF SEPARATE PET AGENT AND MRI AGENT. MARTY, I BELIEVE THAT'S FOR YOU. >> IF YOU CAN LOOK AT PET MR CURRENTLY, YOU HAVE EVERYTHING REGISTERED NICELY, PELVIS, IN THE BRAIN YOU CAN ARGUE YOU HAVE ELABORATE WAYS OF CO-REGISTER THINGS, THAT'S THE MOST BASIC THING. IN ADDITION TO THAT, YOU CAN LOOK CAREFULLY AT WHERE YOUR PROBES ARE GOING, YOU CAN QUANTIFY AMOUNT OF MR PROBES BY USING A STANDARD CURVE AGAINST A PET AGENT WHICH YOU CAN MEASURE QUANTITATIVELY IN VIVO. RELACKSIVETYS YOU GET IN TISSUE FROM MR AGENTS ARE UNPREDICTABLE BECAUSE YOU DON'T KNOW CONCENTRATION OF YOUR AGENTS DUE TO PHARMACOKINETICS BUT WITH PET AGENTS YOU CAN GET A ACCURATE QUANTITATIVE AMOUNT THAT YOU CAN RELATE TO MR. THAT'S AN ADVANTAGE THERE, NEVER BEEN DONE. BUT I THINK YOU CAN DO THAT. THAT'S A LITTLE BIT TIP OF THE ICEBERG. A LOT OF POSSIBILITY. >> THE SECOND QUESTION IS ULTRASOUND. THE QUESTIONER ASKS N THERE MAYBE QUESTIONS TRANSLATING BETWEEN RODENT AN HUMAN STUDIES AND ONE HAS TO DO WITH PENETRATION AND QUESTIONER ASKS WHETHERING ISNAL DETECTION TECHNIQUE OVERCOMES THE HURDLES. DR. EM NO. >> IT'S NOT A FULL BODY IMMA'AMING SYSTEM SO IT WILL REMAIN AS SUCH -- DR. EMELIANOV. IT NICELY MATCHES THE PENETRATION OF ULTRASOUND. BECAUSE WHAT YOU DO IS YOU HAVE TOO IRRATE I DIDN'T DO TISSUE WITH NOT BALLISTIC BUT SCATTER PHOTONS, OUR BODY USING NEUROINFRARED LIGHT IRRADIATION IS NEARLY TRANSPARENT FOR THAT, GENERALLY SPEAKING, IN THE RESEARCH COMMUNITY THAT COMBINES TECHNOLOGIES WE BELIEVE THREE SEN METERS DEPTH IS POSSIBLE AND THERE'S CLINICAL APPLICATIONS FOR THAT. IF YOU USE CONTRAST AGENTS ULTRASOUND AND OPT MICE, THAT'S HARD AREA OF RESEARCH GENERALLY. I BELIEVE IT COULD BE EXTEND TO FIVE CENTIMETER DEPTH. THERE'S PLENTY OF OBLIGATIONS WHERE THAT IS IMPORTANT. >> (INAUDIBLE) FROM NHLBI. THANK YOU FOR THE WONDERFUL PRESENTATIONS. I ENJOYED IT. IF I LOOK IN THE MONOCLONAL IMAGING CONTRAST DATABASE WE SEE THOUSAND PLUS CONTRAST AGENTS DEVELOPED. MOST ARE ARE PROBABLY DEVELOPED UNDER ACADEMIC INTERESTS. BUT A NUMBER HAVE EXCEPTIONALLY GOOD IN VIVO DATA. WHAT ARE HURDLES FOR TRANSLATION TO HUMAN SUBJECTS STUDY WITH THESE PROBES? WHAT GAP IMAGE DO YOU THINK FILL IN TO THESE TRANSLATIONAL EFFORTS? >> I THINK THE LAST IS 5,400 SOMETHING IMAGING AGENTS, OR CONTRAST AGENTS, IN THE DATABASE PUBLISHED IN THE LITERATURE. 50 OF THEM ARE USED IN CLINICAL SETTING THAT HAVE BEEN IMPROVED IN RAREIOUS FORMULATIONS BY THE FDA. IN VARIOUS FORMULATIONS BY THE FDA. >> I DON'T HAVE AN ANSWER BUT I HAVE A SIMILAR INTEREST IN THE QUESTION. ONE THING IS HUMAN HE WILLMENT, PASSION AN DRIVE TO PUSH THROUGH THOSE HURDLES. THAT'S HARD TO COME BY, IF YOUR PASSION IS CHEMISTRY, IT'S NOT SALESMANSHIP IN THAT SENSE. SO I THINK WE NEED EASY TO GENERATE PARTNERSHIPS OF PEOPLE WHO ARE DRIVING FORCE TYPE OF PERSON TO WORK WITH MORE TECHNICAL PEOPLE. BUT I THINK THE CONCEPT OF THE KILLER APP APPLIES HERE AS WELL. WE'RE FINDING THAT WE FINE WE KNEW ABOUT NIDDK R APPLICATIONS WHEN WE START FINDING MOLECULAR TARGETS WE KNOW VERY LITTLE ABOUT THE DISEASE, ESPECIALLY THE DISEASE IN PEOPLE. SO FROM MY POINT OF VIEW WHAT THAT SAYS IS WE NEED TO DO ENORMOUS RESEARCH, WE NEED TO BE MUCH MORE BROAD ABOUT TYPES OF REAGENTS WE TEST, IN DIFFERENT DISEASES AND DIFFERENT CIRCUMSTANCES. I THINK WE HAVE BEEN TOO SILOED MAYBE. >> IS THERE NEED FOR IMAMMING OF MECHANISMS OF DISEASE, DOES THAT REQUIRE MULTI-COLOR APPROACHES YOU CAN LOOK AT MULTIPLE AGENTS AT THE SAME TIME? >> YES. AND I THINK WE SHOULD LEARN TO TRUST YOU HAVE DATA. THIS IS SOMETHING AS IMAGING PEOPLE WE THROW OUT STUFF THAT DOES THEN SEEM TO GO ALONG WITH THE DISEASE OR WHATEVER. THIS INFORMATION SHOULD ALLOW US TO ASK QUESTIONS ABOUT THE DISEASE. >> FOR CARDIOVASCULAR THERE'S MANY TARGETS IDENTIFIED AND SO MANY PROBES INVESTIGATED AND AS POINTED OUT, NONE HAVE GONE TO CLINIC. SO THERE'S GOT TO BE SOME BARRIERS THERE. I TALK -- TALKING FROM MY OWN PERSONAL EXPERIENCE, TO TAKE FOR INSTANCE ANTIBODY OR ANTIBODY FRAGMENT TO THE CLINIC, YOU HAVE THE HUMANIZE IT OR PRODUCE A HUMAN ANTIBODY. YOU'RE TALKING 80, $100,000 THERE. THEN GO THROUGH THE CLINICAL TESTING, YOU NEED PARTNER IN INDUSTRY. FOR THOSE WHO ARE THE ACADEMIC TYPES IN ACADEMIC MEDICINE, WE'RE NOT BUSINESS PEEP. THERE ARE PLENTY AT THIS TABLE WHO CROSS SUCCESSFULLY BUT MANY CAN NOT. IT'S VERY DIFFICULT HOW TO DO THIS WHEN YOU HAVE A CANDIDATE PROBE THAT LOOKS LIKE IT COULD BE USEFUL AND IMPORTANT CLINICALLY. I WOULD ALSO MENTION WHEN PEOPLE WRITE GRANTS, IT MIGHT BE USEFUL TO SUGGEST IN THE GRANT APPLICATION THERE BE A PATHWAY. IF IT'S FOR CLINICAL APPLICATION, IF THESE OOH DOWN THE ROAD, PATHWAY HOW THIS MIGHT EVENTUALLY GO THAT ROUTE, SO THAT YOU CAN MORE QUICKLY MOVE BEYOND MICE WE HAVE BEEN DOING MICE A LONG TIME, MAYBE WE NEED TO MOVE ON. >> I GUESS AT THE RISK OF STATING THE OBVIOUS, IT'S ABOUT MONEY. I DON'T KNOW IF IT'S SO MUCH THE MOTIVATION, WE HAVE VERY MOTIVATED YET ASSISTANT PROFESSORS THAT WOULD LOVE TO TAKE AGENTS AND DATABASE TO THE CLINIC. BUT IT'S JUST UNBELIEVABLY EXPENSIVE TO DO IT. EVEN WHEN YOU HAVE A GOOD AGENT LIKE WE THINK WE HAVE SOME GOOD AGENTS LIKE THAT ONE AGENT THAT I SHOWED THAT DUAL MODALITY WHERE YOU COULD STAGE THE PATIENT DAY ONE AND THEN OPERATE ON THEM AND PREVENT POSITIVE MARGIN, WE PUT IN A BIG NIH GRANT TO DO THAT AND IT CAME BACK AS LOW IMPACT BECAUSE THERE'S NO SENSE IN PREVENTING A POSITIVE MARGIN IN A GUY WITH PROSTATE CANCER BECAUSE HE'S AN OLE GUY ANYWAY. LITERALLY. SO EVEN WHEN YOU HAVE EVERYTHING LINED UP, IT'S ABOUT THE MONEY. THE REASON THAT THAT HAPPENED WAS PROBABLY FUNNED TEN YEARS AGO BUT IT'S GETTING MORE CHALLENGING. SO I THINK THERE ARE A LOT OF GOOD AGENTS AND EVERYBODY HERE WOULD LOVE TO SEE ALL THE THINGS THAT WE DO PUT IN PATIENTS BUT IT'S JUST TOO EXPENSIVE. THERE'S REGULATORY REQUIREMENTS, GMP SYNTHESIS TOXICITY, THREE DIFFERENT SPECIES, ET CETERA. IT'S -- YOU GET UP CLOSE TO $10 MILLION TO TAKE SOMETHING TO THEICALLY THICK. WE JUST CAN'T DO IT SO I THINK THAT'S THE WAY I LOOK AT IT. >> I THINK YOU -- (INAUDIBLE) I'M SORRY YOU JUST SAID $10 MILLION IN CLINIC. I THINK THAT IS PROBABLY A BIT TOO HIGH FOR A NUMBER. IT'S EXPENSIVE, AGREE WITH YOU BUT 10 MILLION -- >> FOR IN MAN STUDY, MAYBE FEW MILLION, LESS THAN 10 MILLION. FOR PHASE 1 STUDY, MAYBE 3 MILLION. IF YOU WANT TO TAKE A DUAL MODALITY OR HOW ABOUT NANOPARTICLE? UP TO TAKE NANOPARTICLE? THAT'S 20 MILLION. SO YOU HAVE TO D&O DO -- YOU PROBABLY HAVE TO DO CHIMPANZEES OR SOMETHING. SO IT'S JUST TOXICITY STUDIES, GMP OR LIKE THOSE THAT PLASMID I SHOW, THAT ASAD IS HELPING GENERATE, WE HAVE TO DO TOXICITY ON IT, IT'S A GENE THERAPY, YOU HAVE TO HAVE A COMPANY INVOLVED WITH DEEP POCKETS TO DO IT. I CHALLENGE FOR LESS THAN $10 MILLION. DR. MORISCA CAN COMMENT, HE HAS DIRECT EXPERIENCE WITH THIS. >> YOU'RE GOING TO STEAL L MY THUNDER FOR THE AFTERNOON BUT SMALL MOLECULE, I AGREE IN TERMS OF MILLION OR SO. BUT WHEN YOU GET INTO THE TOXICITY PACKAGES THAT ARE REQUIRED FOR POTENTIAL BIOLOGICS AND THEN TO ACTUALLY PROCEED, YOU -- IT'S ALL ANT THE MONEY -- ABOUT THE MONEY. I AGREE. >> FROM THE RESEARCH IMMUNITY PERSPECTIVE, IS THERE ANYTHING WE SHOULD BE THINKING ABOUT FROM THE RESEARCH SIDE? DOES QUANTIFICATION MAKE THE TRANSITION BARRIER LOW E ARE THERE TYPES OF SITUATIONS WE CAN HELP WITH TO HELP INCREASE THAT ABLE TO TRANSLATE? OR IS IT GOING TO COME DOWN TO WHETHER CMS WILL REIMBURSE? >> STANDARDIZATION. I HAVE BEEN WORKING NANOPARTICLES FOR TEN YEARS AN THREE WEEKS AGO P DOC IN NANOPARTICLE SYNTHESIS, 40 PAPERS RANDOMLY FOR THE LITERATURE, AN SPENT THE ENTIRE SUMMER TRYING TO REPRODUCE THEM. WHAT PERCENT OF ALL PAPERS THAT THEY TOUCHED WERE REPRODUCIBLE? THESE RANDOMLY PICKED. THREE OUT OF 40. >> THEY WERE RANDOMLY PICKED. THERE ARE NO STANDARDS FOR NANOPARTICLE SYNTHESIS, NO STANDARDS THAT YOU CAN PLACE ON SMALL MOLECULES YOU CAN PLACE ON NANOPARTICLE AN TRYING TO REPRODUCE THE THEM. WHEN YOU SAY WHAT IS THE PROBLEM T RESOURCE BIN WHERE NIH BUDGETS SHRINK AT RIDICULOUS RATES, I LOST 30% THE LAST FIVE YEARS ON CUTS. THERE GOES FOUR POST DOCS, THERE GOES THIS T. BASIC SCIENCE HAS TO BE STANDARDIZED AND THERE'S A LOT OF TERRIFIC EFFORTS HERE BY NIBIB. AND P NCAT DATABASE. BUT IT'S DRYING UP. THERE'S A WILL. THERE SHOULD BE A WILL POWER BEHIND IT. THAT IS FUNDING. >> ONE MORE QUESTION, WE'RE GOING TO END ON A POSITIVE NOTE. >> SO FOR NEXT QUESTION SO ONE MORE REASON IS BECAUSE (INDISCERNIBLE) SO MEASURED AND SO MANY MATERIALS INDUCED IT'S DIFFICULT (INAUDIBLE) THE NANOPARTICLES. AND ALSO NOW IN NIH FDA, BEING ESTABLISHED TO DETERMINE TOXICITY OF -- AND MORE THAN FIVE FOLD IMAGING AGENT HAVE BEEN PUBLISHED IN THE LITERATURE THE MOST ARE SIMPLE COMPOUNDS PET INPECKTOR IMAGING AGENT, 32% MR AGENT. AND (INAUDIBLE) AGENT SEVERAL PERCENT. FROM PAST TEN YEARS LESS THAN -- NO MORE THAN TEN IMAGE AGENTS HAVE BEEN APPROVED BY FDA, NO NANOPARTICLES HAVE APPROVED BY (INAUDIBLE). SO THAT'S OUR DATA. >> I THINK WE ALSO ONE OTHER QUESTION ON THE INTERNET, IF YOU WOULD LIKE TO ASK THE QUESTION. >> FOR THOSE OF YOU WHO SHOWED SLIDES TRYING TO PROMOTE THE USE OF PARTICLES, YOU MENTIONED ONE OF THE USE IS MIGRATION STUDIES STEM CELL MIGRATION OR OTHER CELL MIGRATION, ONE OF THE POWERS OF TO USE MARTY'S CLASSIFICATION, LOW MOLECULAR WEIGHT LIGANDS IS THERE SUBPHARMACOLOGIC. AND SINCE THE NUMBER OF PARTICLES ARE DIFFICULT TO CONTROL, I HAVE SEEN SOME ARTICLES WHERE THEY HAVE SHOWN CELL MOBILITY BEING RETAINED BUT I DON'T SEE TOO MANY VALIDATION STUDIES SHOWING THE SIGNALING CAPACITY OR IMMUNE FUNCTION CAPACITY BEING RETAINED SO THE QUESTION IS HOW CONFIDENT CAN WE BE THAT THE PARTICLES ARE -- DON'T INTERFERE, DON'T PERTURB THE NORMAL FUNCTION OF THE CELLS >> TOM. >> I WILL HAS TO BE TESTED. THERE WAS CONFERENCE THE OTHER WEEK STRICTLY RELATED TO NANOMEDICINE. I NOTICE ALL THE TALKS, EVERYBODY MORE OR LESS HAD AN MTT ASSAY TO MACK SURE CELLS AREN'T KILLED THEN DO OTHER ASSAYS TO SEE IF COMPLIMENT WAS ACTIVATED. I WAS IMPRESSED BY THAT SO THERE IS AWARENESS THAT HAS TO BE TESTED. SO ANY KIND OF PARTICLE, YOU'RE RIGHT. YOU'RE GOING TO DISRUPT A FUNCTION TO A CERTAIN EXTENT SO IF YOU TESTED MAKE SURE YOU'RE AWARE YOU'LL PROBABLY BE OKAY. BUT IT HAS TO BE CONSIDERED. >> WE FOUND THE SAME THING. YOU STAY UNDER 5 TO 6 NANOMETERS THEY GET RENALLY CLEAR SOD THAT'S NOT GOING TO BE THE LONG TERM ISSUE. IT'S THE BIGGER ONES THAT HAVE PROBLEM. >> SO TO SUMMARIZE YOUR ANSWER EVERY NEW PROPOSED ARTICLE HAS TO BE INDEPENDENTLY VALIDATED Q. ABSOLUTELY. YOU HAVE ONE ATOM ON A MOLECULE, YOU HAVE TO TAKE THAT THROUGH TOX GMP, ET CETERA. >> WE THINK GOLD AND CARBON HAVE PROMISE BECAUSE WHAT'S BEEN DONE SO FAR. THE BAR IS HIGH. >> I DON'T WANT TO EAT TOO MUCH INTO LUNCHTIME, WE'RE GOING TO RECONVENE AT 1:05, WE'LL HEAR FROM SOME OF THE PEOPLE ON THE COMMERCIAL END. I JUST LIKE TO THANK ALL OUR SPEAKERS FROM THIS MORNING. FOR AER VERY INTERESTING DISCUSSION. THANKS. [APPLAUSE] LET'S START SESSION 3. CURRENT CHALLENGING AND NEEDS FOR INDUSTRY PHARMACEUTICAL COMPANIES. THE FIRST SPEAKER IS DR. PAULA JACOBS FROM NCI. THE TITLE OF HER TALK -- >> I DON'T KNOW HOW I ENDED UP BEING IN A COMPANY. IS THIS ON? WHAT I'M GOING TO TALK ABOUT IS NCI SPECIFIC THAT'S WHERE I'M COMING FROM. I HAVE TO FINANCIAL DISCLOSURES. LY TALK ABOUT OFF LABEL INVESTIGATIONAL USES. NCI SUPPORTS MOLECULAR IMAGING FOR CANCER, OUR INTRAMURAL PROGRAM AN RESEARCH LABORATORIES IN ADDITION WE HAVE A SMALL ANIMAL IMAGING PROGRAM IN FREDERICK USED BY OTHER INSTITUTES IF THEY WOULD LIKE FULLY I EQUIPPED WITH WITH EVERYTHING YOU WOULD WAN WE HAVE EXTRAMURAL GRANTS AND CONTRACTS, THEE ARE THE DIVISIONS LISTED AT NCI PRIMARILY DEAL WITH IMAGING. MY DIVISION IS DIVISION OF CANCER TREATMENT DIAGNOSIS WHICH IS THE LARGEST DIVISION BUT THE OTHERS ALSO IMAGING. NON-CANCER IMAGING IS SUPPORTED BY THE REST OF NIH. I'M GOING TO TALK ABOUT SOMETHING CALLED THE EMPERIMENTAL THERAPEUTIC PROGRAM. GRANTS SPECIFIC FOR IMAGING,fRy COOPERATIVE GROUP TRIALS WHICH CAN USE IMAGING, SHARED INDs, AND THIS IS NOT NCI, IT'S FDA BUT I THINK IT'S IMPORTANT FOR PEOPLE IN THIS FEEL TO KNOW ABOUT HOW DO YOU GET ORPHAN DRUG DECISION NATION AND FUNDING? THE NEXT PROGRAM IS NOT A GRANT PROGRAM. IT PROVIDES ACCESS TO NIH RESOURCES AN DEVELOPMENT OF EXPERTISE, INTEGRATE AS VARIETY OF PROGRAMS EXISTED OVER THE YEARS DATING BACK SEVERAL DECADE S. FULL TEAM SUPPORT FOR PROJECTS ACCEPTED. THE PI HAD PROJECT INVOLVEMENT BUT IT'S NOT A GRANT PROGRAM, WE DON'T GIVE MONEY, WE DO THE WORK. DO RESOURCES CURRENTLY SPORE INVESTIGATIONAL DRUGS AND BIOLOGICS, INVESTIGATIONAL IMAGING AGENT,ACADEMIC BIOTECH ABOUT PHARMA P PROJECTS PHASE 0, 1 AND 2 CLINICAL TRIALS, HIGH THROUGH PUT SCREENING, LEAD OPTIMIZATION BUT DOESN'T SUPPORT BAY SECOND RESEARCH. SO YOUR HIGH THROUGH PUT SCREENING WOULD BE TO A KNOWN TARGET. THAT'S FOR RO-1s. THIS IS WHAT WE MASHED TOGETHER FOR THE NCI THERAPEUTICS PIPELINE WHERE WE RUN THROUGH DRUG DISCOVERY EARLY DEVELOPMENT AND FULL DEVELOPMENT ACTIVITIES. THE RESOURCES ARE MULTI-INTERDISCIPLINARY CLINICAL TRANSLATIONAL RESEARCH TEAMS, IT HAS EARLY ACCESS TO LEADING EDGE TRANSLATIONAL TECHNOLOGY. PKPD MODELING TOXICOLOGY AND SAFETY PHARMACOLOGY, GMP SCALEUP INCLUDING BUY LODGE iS -- BIOLOGICS MANUFACTURING FACILITY IN FED RICK. IMAGING FOR BIODISTRIBUTION. DEVELOPMENT AND PHARMACO -- DEVELOPMENT AND VALIDATION OF CLINICAL ASSAYS, IS AN ACTIVE PROGRAM IN CTCs, CIRCULATING TUMOR CELLS. YOU CAN GET THE NEXT BY GOING THROUGH OUR WEBSITE AND BASICALLY ANYONE CAN APPLY ACADEMIC, GOVERNMENT INDUSTRY NATIONAL INTERNATIONAL. THERE ARE THREE CYCLES A YEAR FOR SUBMISSIONS. ONE IS JUST PAST HERE, APPLICATION PROCESS IS SIMPLE, IT'S FIVE PAGE APPLICATION BULKED UP BY APPENDICES, ONE THING HERE IS THAT WE HAVE TO KNOW EXACTLY WHAT YOU'RE ASKING NCI TO DO. WE'RE NOT ASKING FOR YOUR RESEARCH PROPOSAL, A LOT WILL COME IN SAYING WE WOULD LIKE TO MAKE GMP DRUG AND DO IND ENABLED TOXICOLOGY, THAT SPECIFICITY. IT'S EVALUATED SIMILAR TO A GRANT EXCEPT THAT IT HAS TO FIT ALSO INTO THE NCI MISSION, IT HAS TO BE CANCER, IT NEEDS TO BE SOMETHING WE THINK NOT BEING DONE FOR EXAMPLE WITH INDUSTRY. WE OWN DO ANOTHER EGFR ANTIBODY. SPECIAL CONSIDERATION TO UNMET NEED INCLUDINGABLE TARGET, MALIGNANCIES AN PEDIATRIC CANCERS. THE APPROVAL STARTS WITH ADVISING PAY ECONOMIES WHO TAKE IN ALL APPLICATIONS AND RANGE THEM. ESSENTIALLY PROVIDED TO TOP TIER AND THE REST. THERE IS AN OBVIOUS BREAK IN SCORES BETWEEN THREE AND SIX PER CYCLE. THOSE DEPENDING ON WHETHER THEY'RE PRIMARILY DISCOVERED HIGH THROUGH PUT SCREENING OR DEVELOPMENT LIKE GMP AN TOX GO TO DIFFERENCE INTERNAL COMMITTEES WHERE WE LOOK AT OVERLAP. THOSE COMMITTEES MAKE A RECOMMENDATION THAT GOES TO SOMETHING CALLED THE SENIOR ADVISORY COMMITTEE WHICH DECIDES ON ALLOCATION OF RESOURCES. THIS IS WHERE THE RUBBER HITS THE ROAD BECAUSE WE HAVE LIKE EVERYONE ELSE L LIMITED MONEY. I'M IMAGING REPRESENTATIVE ON ALL THREE COMMITTEES. SO I HAVE TO SEE ANYTHING THAT WE DO FOR ENERGY. EXAMPLE PROJECTS WE'RE SCREENING NATURAL PRODUCT LIBRARIES FOR INHIBIT ACTIVITY AND SPECIFIC PATHWAY, IDENTIFYING CHEMICAL ASK FOLDS AGAINST A TARGET OR PATH. PRE-CLINICAL EVALUATIONS IN SELECT CELLS AN MODELS, IND DIRECTED FARM TOX. GMP SYNTHESIS AND CLINICAL TRIALS. CURRENTLY THERE ARE FOUR IMAGING PROJECTS, THREE WHICH ARE OPTICAL AND ONE IS A PET AGENT. AN EXAMPLE OF ONE, RECEPTOR TARGETED AGENERAL FOR TUMOR MARGIN DETECTION DURING THE SURGERY. THIS WAS THE REQUESTED NCI WAS TO ONMIZE THE REACTIONS, TIME, TEMPERATURE AND RATIOS, VERIFY THE TARGETING IN VITRO AND IN VIVO AND THAT THE CHANGES IN THE ANTIBODY DID NOT -- THE CHEMISTRY DID NOT ALTER BIOLOGICAL ACTIVITY TOO MUCH. ESTABLISH PURRTY, GET FORMULATION, TRANSFER THE BIOLOGICS GMP CONTRACTOR OR MANUFACTURING AND DO IND DIRECTED TOXICOLOGY. THIS PROJECT ASSISTS WITH IND FILING; THIS CASE PI WANTED -- HE WILL DO THE TRIAL INFILLED THE IND SO WE WILL DO THAT AND HAND IT BACK TO HIM. AND IT'S NOW PRE-IND MEETING STAGE MEET WITH THE FDA, DISCUSS TOXICOLOGY REQUIRED WHICH DETERMINES HOW MUCH WE MAKE IN THE GMP FACILITY. ONE THERAPEUTIC CAME TO US WHICH WAS A PROTEIN DRUG THAT WAS SPECIES SPECIFIC BUT THERE'S NO MEANINGFUL TOXICOLOGY YOU CAN DO. THEY WENT THROUGH EVERY NON-HUMAN PRIMATE THEY CAN FIND AND ABSOLUTELY NOT SPECIFIC, ONLY HUMAN TISSUES. WE DETERMINED IMAGING BEST PROTECT HUMAN SUBJECTS BECAUSE YOU CAN START WITH A LOWER DOSE. YOU CAN DO BIODISTRIBUTION TO DETERMINE OFF TARGET ISSUES AN P THEN PROCEED TO THERAPEUTIC. WE PREPARED KEY LATES FOR SPECK AND THE PI DID THROUGH THIS PROJECT BECAUSE HE FOUND A COMMERCIAL PARTNER THAT WAS A SUCCESS. METRICS HERE ABOUT WHAT KIND OF PROJECTS. THIS IS -- WE HAVE A TOTAL OF 27 ACTIVE PROJECTS IN THE DISCOVERY AREA, 23 IN DEVELOPMENT. THERE ARE TOTAL APPLICATIONS, 419 TO DATE. WE FIRST STARTED IN 2009. HALF ACADEMIC, THIRD BIOTECH, NON-PROFITS PHARMA AND GOVERNMENT, WE WILL FUND NIBIB WOULD LIKE TO PUT ONE IN, WE'LL MOVE TO THAT TOO. THAT STAGE GATE CLINICAL CANDIDATES PHASE 1 AND 2, SCREENING, LEAD DEVELOPMENT, IMAGING 8% SMALL MOLECULE -- BIOLOGIC 38%. SHIFT GEAR NOW, I'M GOING VERY FAST BUT YOU CAN GET IN TOUCH AFTERWARDS. GRANT FUNDING OPPORTUNITIES THAT HELP IMAGING. GENERAL FUNNING YOU SHOULD BE AWARE OF THE GENERAL NOTICES FOR NIH AND NCI. SPECIFICALLY FOR EARLY PHASE TRIALS IMAGE GUIDED INTERVENTION AND IT'S AN UNUSUAL R-21 BECAUSE IT H SUPPORT 500,000, IT MUST BE TRIAL YOU CANTICLE AND SARA I WOULD LIKE TO DO WORK FIRST, YOU HAVE THE IND OR BE READY TV IT IMMEDIATELY OR ELSE IT CAN BE AWARDED -- CAN BE AWARDED. WE HAVE RO-1 IMAGE GUIDED DELIVERY AND CANCER STANDARD POLICIES. QUANTITATIVE IMAGING FOR EVALUATION APPROXIMATE RESPONSES TO CANCER THERAPIES, THIS IS A COOPERATIVE AGREEMENT, UO-1, THIS IS THE DEVELOPMENT SHARE QUANTITATIVE METHODS TO MEASURE TUMOR RESPONSE TO THERAPY. ACADEMIC INDUSTRIAL PARTNERSHIP, IT'S NOT LIKE SBIR BECAUSE IT IS TRULY AN RO-1, IT IS RESEARCH BUT REQUIRES ACADEMIC PARTNER AND INDUSTRIAL PARTNER TO PARTICIPATE AND UNLIKE SBIR IT CAN BE A LARGE COMPANY AND IT CAN BE AN INTERNATIONAL COMPANY. NCI COP RATIVE QUESTIONS, THOSE ARE VERY INTERESTING LITTLE SERIES OF RFAs, THEY'RE CLOSE THIS YEAR AND WE'RE WORKING ON THE ONES FOR NEXT YEAR, SOME WILL BE IMAGING, WE ROLE A COOPERATIVE GROUP TRIAL SYSTEM THEY CONDUCT LARGE SCALE CLINICAL TRIALS, THEY'RE TEN GROUPS, THEY STARTED BACK IN THE 50s, THEY ARE NOW DISEASE OR YENNED RADIATION THERAPY SURGERY IMAGING ALL INDIVIDUAL GROUPS, THEY ARE TO BE RESTRUCTURED NEXT YEAR TO FOUR ADULT ONE PEDIATRIC WHICH WILL CHANGE VERY DRAMATICALLY. RIGHT NOW WE HAVE TEN, THAT'S 3,000 INSTITUTIONS, 4,000 INVESTIGATORS AND ENROLLED 25,000 PATIENTS ANNUALLY. WHY DO WE SUPPORT THIS? BECAUSE WE -- ESPECIALLY ON QUESTIONS NOT A PRIORITY FOR SPRY INDUSTRY WE DO A LOT OF ORPHAN DRUGS AN RARE DISEASES. THEY'RE ORIENTED TO A DISEASE MANAGEMENT AND NOT AGENERAL SPECIFIC MORE LIMITED BY MARKETING. WE CAN DO A TRIAL THAT COMPARES TO COMMERCIALLY AVAILABLE THINGS FROM TWO DIFFERENT COMPANIES, COMPANIES DO NOT DO THAT. EFFECT TENSIVE INVOLVEMENT OF THE ENTIRE ONCOLOGY COMMUNITY AND DESIGN DEVELOPMENT AND CONDUCT OF THESE TRIALS. ALL OF THEM ORIGINATE FROM MANAGEMENT OF THE GROUPS. SHIFTING GEARS AGAIN, I WOULD LIKE TO TALK SHARED INDs. BACK TO THE PURPOSE OF IND IS AN EXEMPTION FROM LAW REQUIRING APPROVED MARKETING APPLICATION FOR DRUGS TO ALLOW CLINICAL TESTING. IT IS TO ASSESS PROPOSED CLINICAL PROTOCOL OR PROTOCOLS NOT UNNECESSARILY RISKY, THE FDA WILL EVALUATE PRE-CLINICAL DATA FOR SAFETY, EVALUATE THE INVESTIGATOR'S QUALIFICATIONS, EVALUATE DRUG PURITY. INFORMATION REQUIRED FIRST AND FOREMOST A CLINICAL PLAN, CLINICAL PROTOCOLS, INVESTIGATOR OBSERVATION. CHEMISTRY MANUFACTURING CONTROL INFORMATION. PHARMACOLOGY AND TOXICOLOGY STUDIES IN ANIMAL SPECIES. PREVIOUS HUMAN EXPOSURE INFORMATION. PHARMACEUTICALS WE NEED DOSE SYMMETRY. ONE IMPORTANT ASPECT FOR THIS IMMUNITY IS THAT ALL THE CLINICAL ASPECTS CAN BE IMPORTED FROM SOMEONE ELSE'S IND BY LETTER OF REFERENCE. THIS CAN BE EXTREMELY HELPFUL. IT'S CALLED TECHNICALLY CALLED A LETTER OF RIOT OF REFERENCE BUT EVERYBODY CALLS LETTER OF AUTHORIZATION OR CROSS FILE LETTER. IT INCORPORATES SPECIFIED SECTIONS FROM ONE INT, DMF OR MDA TO ANOTHER BY REFERENCE. INFORMATION INFORMATION IS NOT REPEATED IN IDN AND NOT PROVIDED TO THE NEW APPROXIMATELY CAN'T. IF YOU HAVE A LETTER AND WANT TO GIVE INFORMATION YOU CAN BUT NOT REQUIRED TO. IT TELLS THE FDA THEY CAN OPEN UP THE OLD IND WHILE LOOKING AT THE NEW ONE AND PRETEND IT'S ALL ONE. ALL THE NEW APPLICANT NEEDS IS A LETTER. IMPORTANT THING HERE FOR THOSE WHO HOLD INDs, YOU MUST BE WILLING TO GRANT LETTERS TO YOUR COLLEAGUES. THE HOLDER OF THE ORIGINAL INT HAS NO RESPONSIBILITY FOR THE IND. THE NEW IND IS INPEP DENT IND RESPONSIBLE FOR MONITORING IT, PUTTING IT TO THE FDA AND EVERYTHING ELSE SO THERE'S NO DOWN SIDE TO YOU'RE PROVIDING IT. AN EXAMPLE HERE IS I HAVE GIVEN PROBABLY A 40 OR 50 LETTERS TO AN FLT IND THAT I HAVE, AN INDUSTRY INVESTIGATOR, SPECIFY AUTHORIZEDDED FOR FARM TOX INFORMATION FOR PREVIOUS HUMAN EXPERIENCE, IT NOTES CNC REFERENCE IS NOT AUTHORIZED. IT'S A PET AGENT, THE CHEMISTRY HAS TO BE FILED SOMEWHERE. SOME COMMERCIAL HAS DMS AND THEY MIGHT BE ABLE TO SUPPLY YOU, YOU CAN SUBMIT YOUR OWN CMC OR USE COMMERCIAL FIRMS TO TO THIS. THE LETTER IS FILEDD TO MY IND AND THE NEW IND. THE ADVANTAGES OF ARE QUITE INTERESTING, IT SAVES THE LIVES OF ANIMALS WHICH THOSE OF US WHO HAVE TO DEAL WITH TOXICOLOGY STUDIES WE KNOW WE HAVE TO USE ANIMALS BUT WITH WE TRY TO KEEP IT AS LITTLE AS WE CAN. SO YOU AVOID REPETITIVE TOXICOLOGY STUDIES AND YOU SHOULDN'T HAVE TO BE 17 DIFFERENT ACUTE STUDIES FOR THE SAME TRUCK. IT SAVES THE THE WORK NEEDING TO GLOBALIZE I AND PRESENT CERTAIN SECTIONS OF YOUR IND AND I AVOIDS UNCERTAINTY, BECAUSE THE FDA ACCEPTED INFORMATION IN THE ORIGIN MA'AM IND AND P OR DMF AND P THE FDA KNOWS THEY REVIEWED IT. SO THEY DON'T NEED TO WASTE TIME REVIEWING IT AGAIN. THEY CAN THEN FOCUS REVIEW ON THE CLINICAL TRIAL. ADDITIONAL RESOURCES FROM NCI IN THIS REGARD. WE HAVE DOCUMENTS ON OUR WEBSITE, WITH A FULL SET OF SOPs TOWARD THE USPA 23 ENVIRONMENT THAT ANYONE CAN USE TO CUSTOMIZE FOR MANUFACTURING. THE VAST MAJORITY OF THESE ARE NOT DRUGS SPECIFIC, THEY'RE THINGS LIKE HOW TO RECEIVE RAW MATERIAL THOUSANDS DO AN AREA CLEARANCE, THAT SORT OF THING. INVESTIGATOR BROCHURES FOR THE INDs WE HAVE SUMMARIZING THE INFORMATION WE UPDATE SOMETIMES EVERY OTHER YEAR QUESTION PENDING HOW MANY WORK. WE HAD FULL TOXICOLOGY REPORTS. ALSO GET SOME HAND HOLDING ADVICE I, TALKED INVESTIGATORS THROUGH FILING FOR IND AND AVOIDING A LOT OF PROBLEMS WITH THE REVIEW. THIS IS THE LAST SUBJECT, I HAVE ABOUT FIVE MINUTES, THIS IS NOT NCI BUT RELEVANT TO OUR COMMUNITY LIKE EXPLORATORY INDs ARE RELEVANT TOWER COMMUNITY. ORPHAN DRUGS OR BIOLOGICS NOT DEVICES INTENDD TO TREAT DIAGNOSE OR PREVENT A RARE DISEASE OR CONDITION OR DRUG NOT PROFITABLE IN 7 YEARS FOLLOWING FDA MARKET APPROVAL. IN OUR COMMUNITY IT WOULDN'T BE RARE. THERE'S PATHWAY AVAILABLE FOR DEVICES,'S NOT IDENTICAL. THE FIRST QUESTION, IS IT RARE. IT HAS TO BE A PREVALENCE DISEASE PRE-LENS LESS THAN 200,000 IN THE US. PREVALENCE, NOT INCIDENCE, THAT'S IMPORTANT TO REMEMBER. ACUTE DISEASES ARE CONDITIONS CAN BE USED IN SOME CASES IF THEY'RE ACUTE LIKE ANTIBIOTIC. DIAGNOSTICS SUCH AS IMAGING AGENTS WOULD BE SUBJECTED TO LESS THAN 200,000 PATIENTS IN THE U.S. ANNUALLY. YOU CAN DO MEDICALLY PLAUSIBLE SUBSETS OF COMMON DISEASES LIKE METASTATIC MELANOMA, IT'S NOT AN ORPHAN DISEASE, METASTATIC MELANOMA IS. YOU CAN'T MAKE UP YOUR POPULATION. IT MUST BE AN ORPHAN,THAT WON'T PASS THE THING. LIMITD TO SUBSET OF DISEASE OR CONDITION, TOXICITY, MECHANISM OF ACTION. IT WOULD NOT BE USED IN THE FULL COMPLIMENT OF THE DISEASE. IF YOU HAVE SOMETHING THAT WOULD ONLY BE GOOD IN RECURRENT PROSTATE CANCER, THAT COULD MEET THE BAR. BUT IF PEOPLE START EWE USING IT IN THE INCIDENCE OF PRIMARY INCIDENCE CASE OF PROSTATE IT WOULD NOT. THE REGULATORY TERM TO DELINEATE WOULD BE TO DELINEATE PERSONS EXPECTD TO USE THE DRUG, IT'S NOT A CLINICAL DEFINITION, IT'S REGULATORY. BENEFITS OF THE DECISION NATION -- DESIGNATION ARE MULTIPLE, FINANCIAL. YOU GET SEVEN YEARS MARKET EXCLUSIVITY, 50% TAX CREDITS FOR A COMPANY. AND A WAIVER OF ALL MARKETING APPLICATION FEES. THIS IS HUGE. IF YOU PUT OUT AN NDA RIGHT NOW WITH CLINICAL DATA IN IT, A BLAND NEW NDA YOU IMMEDIATELY OWE THE FDA $6 MILLION TO FILE IT. I CAN'T LOOK AT IT UNTIL YOU HAVE GIVEN THE MONEY, FOR SOMETHING LIKE A PET AGENT $1.6 MILLION IS PROBABLY 20 YEARS WORTH OF PROFIT, IT'S NOT GOING TO WORK. IT'S ALSO THE FIRST STEP IN FDA COMMUNICATION AND OFFICE THE OOPD IS ORPHAN DRUG OFFICE THERE. IF OUR GET THAT DESIGNATION, IT'S A DESIGNATION, NOT AN APPROVAL, THAT ATRACKS VENTURE CAPITAL TO A SMALL COMPANY THAT'S IMPORTANT. THE REQUEST IS THE SIMPLEST FDA SUBMISSION YOU CAN DO. IT HAS TO BE MADE PRIOR TO SUBMISSION OF APPLICATION BUT IND STATUS DOESN'T MATTER. NOT REQUIRED. PRIVATE CITIZENS I KNOW A NEUROSURGEON WHO HAS DESIGNATION FOR MR CONTRAST AGENT. THAT IS ORPHAN. FOR PROFIT, NOT FOR PROFIT, ANYBODY. THE CHALLENGES MOST NON-REGULATORY. VERY FEW PATIENTS TO STUDY THE NATURAL HISTORY MAY NOT BE UNDERSTOOD. SOME DISEASES 300 PEOPLE IN THE WORLD HAVE THE DISEASE. 'S HARD TO GET A RANDOM EYED CONTROL CLINICAL TRIAL THAT WAY. EFFICACY AND SAFETY DATA SETS ARE SMALL AND FEW EXPERTS. AND REGULATORY POINT OF VIEW, LEGAL POINT OF VIEW THE EVIDENTIARY STANDARD IS THE SAME. THERE IS ROOM FOR FLEXIBILITY, PART OF THE ADVANTAGE IS THEY WILL WORK WITH YOU IN THE VIEWING DIVISION DIVISION TO DETERMINE WHETHER THEY CAN RELAX CERTAIN OF THE REQUIREMENTS. FINALLY, THEY HAVE A GRANT PROGRAM FOR DEVELOPMENT. PROVIDES COMPETITIVE FUNDING FOR CLINICAL RESEARCH OF DISEASES, THERE'S AN RFA ONCE A YEAR. THAT DOES REQUIRE AN ACTIVE IND OR IDE. BUT IT IS AN AREA DIFFICULT TO GET FUNDING FOR THIS KIND OF THING SO THIS IS SOMETHING YOU SHALL BE AWARE OF. DRUGS BIOLOGICALS, EVERYTHING QUALIFIES, $14 MILLION PER YEAR, AND YOU CAN GET 2 TO 400 PER YEAR. RECOMPETITION IS ALLOWED AVAILABLE TO ANYBODY AND AVAILABLE ON THE WEBSITE. EMA HAS A SIMILAR PROCESS, YOU CAN DO A COMMON ONE, AND THAT'S IT. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> GO TO THE NEXT SPEAKER. OUR NEXT SPEAKER IS KAREN MARISCA FROM PHASER. THE TITLE OF THE TALK IS EXPANDD USE OF PET MOLECULAR IMAGING. THE CURRENT TRENDS AND CHALLENGES FROM A PHARMACEUTICAL COMPANY. >> TODAY I'LL TRY TO TO -- THANK YOU FOR INVITING ME. TRY TO GIVE YOU THE INDUSTRY PERSPECTIVE AS COMING FROM A BIG PHARMA INTO HOW WE VIEW MOLECULAR IMAGING IN PARTICULAR PET MOLECULAR IMAGING. PRESENTATION YOU LINE, I WILL INTRODUCE THE PHARMACEUTICAL DEVELOPMENT AND SLIDES. PFIZER STRATEGY INCLUDES SUCCESS, CURRENT TYPE OF TARGETS, TRENDS, EXAMPLES OF PFIZER PET PET EXAMPLES HOW WE USE IT AND TALK TO CHALLENGES THAT WE FACE AND HOW WE SEE THE FUTURE. SO NOT SURE IF YOU CAN SEE THE SLIDE BUT IT'S SHOWING YOU THE LARGEST PHARMACEUTICAL COMPANIES AS OF 2011. THE RANKING OVER THE LAST DECADE. I HAVE HIGHLIGHTED THERE IN RED PHASER THE TOP COUPLE OVER THE LAST DECADE. THANKS TO LIPITOR. WHAT I ADD IS ANOTHER COLUMN, PRE-CLINICAL MOLECULAR IMAGING, PRE-CLINICAL AN CLINICAL ESSENTIALLY, AND HOW ALL THESE BIG PHARMA USE MOLECULAR IMAGING OF ONE SOURCE OR ANOTHER. A LOT IN FLUX RIGHT NOW. I WILL SPEAK TO OUR COMPANY, IT'S BEEN INTERNALIZED WE HAD OUR OWN CAMERAS, RESEN HI WE SOLD OFF AND GOING TO THE EXTERNAL MODEL WHERE WE LOOK AT MOLECULAR IMAGING BUT PARTNERSHIPS AS WE GO FORWARD. A LOT DO SIMILAR TREND IN THE INDUSTRY. TIME AND MONEY PHARMACEUTICAL DEVELOPMENT. IT IS COSTLY, AND TIME AND MUCH IS INCREASING OVER TIME INCREASING CLINICAL TRIALS OVER TIME ONGOING, WHERE DRUG DISCOVERY TAKES 6208 YEARS, AT PFIZER AND DRUG DEVELOPMENT FROM 6 TO 10 YEAR AVERAGE TO GET THROUGH THE iiCLINICAL TRIALS. THIS CAN COST ANYWHERE FROM TEN YEAR TO UP TO 15 YEARS AT PFIZER THESE DAYS. THE COST VARIES PER RESEARCH AREA. THIS SHOWS HALF A BILLION DOLLARS TO UPWARDS OF 1.5 AT PFIZER, SIMILAR BUT VARIES GREATLY DEPENDING ON THE RESEARCH AREA SO ANYWHERE FROM HALF A BILLION TO $2.5 BILLION TO GET A DRUG FROM DRUG DISCOVERY ALL THE WAY THROUGH TO MARKET. LOOKING AT ATTRITION RATES FROM (INAUDIBLE) THEY LOOKED AT 1990 TO 2004 WITH 28,000 COMPOUNDS, PRE-CLINICAL PHASE 1, PHASE 2, PHASE 3 TO REGISTRATION. THE ADISTRIBUTION RATE IS HIGH OBVIOUSLY AND ALL THE SLOPES ARE POSITIVELY FOCUSED SO LOSE PRE-CLINICAL AN ANOTHER SPIKE IN PHASE 2 AREA. BUT I LIKE TO BE MORE POSITIVE SO I LOOK AT PAPER FROM TUFTS. SUCCESS RATES, SIMILAR TREND, TWO FIVE YEAR PERIOD LOOKING AT THE LEFT HAND CHART THERE, FROM 1993 TO 1998 AS WELL AS 1999 TO 2004. YOU SEE A SIMILAR PATH, PHASE 1, PHASE 2, PHASE 3. LAST COLUMN IS A COMBINATION AN SHOWS 16% SUCCESS RATE ALL THE WAY THROUGH THE 50 LARGEST PHARMACEUTICAL FIRMS AN 1700 NEW DRUGS SO THE TREND IS SIMILAR OVER TIME PERIODS BUT THERE ARE DIFFERENCES, IT SWITCHES DEPENDING ON RESEARCH AREA YOU LOOK FOR, NEUROSCIENCE, NOT AS SUCCESSFUL AS SOME OF THE OTHER AREAS AND THEN AS YOU ROOK I PULL OUT THIS ONE ON SMALL MOLECULES VERSUS LARGE MOLECULE BECAUSE OF A LARGE DISCREPANCY, YOU SEE THE LAST COLUMN THERE, 13% SUCCESS RATE FOR A SMALL MOLECULE, COMPARED TO 32 PEST FOR A LARGE MALL CALL, THAT'S BIOLOGICS OR SYNTHETIC PROTEINS ANTIBODIES. BUT THAT CONSIST OF ABOUT 10 TO 15% OF YOUR NEW DRUGS. SO THIS SLIDE IN THERE, THIS JUST EMPHASIZES AGAIN, TIME AN MONEY, WHAT'S THE CRUCIAL STEP? WE FIND AT PFIZER AND OTHERS FINE IS YOUR PHASE 2 DESIGN HAS TO SHOW CLINICAL EFFICACY THE CRUCIAL STEP IN PHARMACEUTICAL DEVELOPMENT. WHY DO DRUGS FAIL? THERE ARE A NUMBER OF REASONS, I PICKED OUT MAJOR ONES, LACK OF EFFICACY, NON-SPECIFIC SIGNIFICANT IMPROVEMENT OVER CONTROL, LACK OF DISCRIMINATION VERSUS CONTROL, NO BENEFIT AS ADD ON THERAPIES YOU'RE ADDING ON. THESE THEORIES WHY THIS HAPPENS AND THE LOW HANGING FRUIT THEORY. WE'RE LOOKING AT NEW TARGETS NOVEL CHEMISTRY, NOVEL BIOLOGY AN IT HAS TO COME TOGETHER. IT'S DIFFICULT TO DO. OBVIOUSLY TOXICITY, SAFETY CONCERNS, PK PROFILES, ONE THING THAT COMES IN PLAY PFIZER OBVIOUSLY BIG PHARMA IS STRATEGIC REASONS WHETHER COMPETITION, INTERNAL OR EXTERNAL. FOR MYSELF I WORK ON A PROGRAM THAT HAS THREE PROJECTS ON SIMILAR PROGRAM. OBVIOUSLY ALL THREE ARE NOT GOING -- THEY'RE COMPETING WITHIN PHASER FOR THAT GOALEN RING. MARKET FAILURE, THE MARKET CHANGES DUE TO DISEASE CHANGE OR INNOVATION YOU CAN HAVE COMMERCIALIZATION FAILURE. SO HOW DOES PET MOLECULAR IMAGING HOW DOES IT HELP IN DRUG DEVELOPMENT? WE CAN LOOK AT A NUMBER OF THINGS. OBVIOUSLY WE CAN SEE WHETHER IT HITS A TARGET, WHETHER IT AFFECTS MECHANISM AND IMPROVE CLINICAL OUTCOME. OBVIOUSLY THESE ARE IMPORTANT POINTS AND DECISION POINTS IN LARGE PHARMA DEVELOPMENT. HOW DOES PFIZER -- BY USING PRECISION MEDICINE. WE DEFINE IMAGING AND GENETIC COMBINED. THIS MITIGATES THE RISK INVOLVED IN CLINICAL TRIALS AND PHARMACEUTICAL DEVELOPMENT. WE'RE IN THE USING PET MOLECULAR IMAGING TO LAUNCH NOVEL TRACERS BUT JUST SUPPLEMENT WHAT WE CAN IN TERMS OF INFORMATION FOR OUR DRUG CANDIDATES. WE ARE IMBEDDED WITH RESEARCH AREAS, PRECISION MEDICINE IN THE MIDDLE, WE HELP OUT A LOT IN NEUROSCIENCE ONCOLOGY, CARDIOVASCULAR BUT IT'S EXPANDING ACROSS THE SPECTRUM OF PFIZER IN TERMS OF HOW WE CAN HELP, WHAT STAGE WE CAN HELP IN PHARMACEUTICAL DEVELOPMENT. WHEN YOU TALK PET IMAGING, WHERE IT BEGAN, WITH WITH TRACER DEVELOPMENT YOU NEED A VALIDATED TRACER, IT'S CRUCIAL FOR SUCCESSFUL CLINICAL TRIALS. SO WE PUT IN FOUR STEPS, TRACER ORIGINS, OBVIOUSLY WE HAD INTERNAL SUPPORT WE HAVE HIGHLY POTENT COMPOUNDS WITH SELECTIVE UPTAKE. EXTERNAL TRACERS, ARE THOSE COMPOUND MORE ADVANCED? ARE THE CNCs COMPLETED, INTs FILED AND CAN WE USE THEM? TRACER QUALIFICATION IS A SECOND STEP. EVALUATE THE TRACERS FOR WHAT WE NEED TO DO. BINDING POTENTIAL TEST RETEST VARIABILITY, PK AND SEE IF IT'S FIT (INAUDIBLE). WE LOOK EXPRESSING DISEASE VERSUS HEALTHY STATE AND WHETHER WE CAN USE IT AS POTENTIAL STAGING AN MONITORING OF DISEASES, TARGET ENGAGEMENT IN THE OCCUPANCY STUDIES. WE KNOW WHAT IT TAKES FOR TRACER DEVELOPMENT, IT'S BEEN UNDERFOR A LONG TIME THE CHARACTERISTICS OF THE TARGETS THAT ARE CONSIDERED TO BE IMAGEABLE ARE KNOWN. WE KNOW THE RADIO ISOTOPES WE HAD TO CHOOSE FROM, WE HAD TO SELECT WITH A LOOK TO THE FUTURE. WE ALSO THINGS WE KNOW THE RADIO SYNTHETIC CHEMISTRIES THAT GO ON ARE OPTIMIZED AND SOME AUTOMATED THIS IS IMPORTANT FOR GOING TOWARDS CLINICAL GMP, CGMP KIND OF WORK TOWARDS THE CLINIC. WE ALSO KNOW RADIO TRACERS ONLY NEED TO BE PREPARED AND SAFE STERILE FORMULATION AND STABLE IN VIVO USE THAT YOU'RE GOING TO USE THEM, SINCE PFIZER IS EXTERNALIZING ALL THIS, IT'S -- WE'RE THRUSTING UPON RELIABLE PARTNERSHIPS GOING FORWARD. WHEN WE DO COME ACROSS A NOVEL TRACER THAT WE WE WOULD LICK TO EVALUATE ERRANTLY A COMPUTER PROGRAM IF WE TIME AN MONEY, THIS IS AN EXAMPLE FROM NEUROSCIENCE FROM PFIZER DIFFERENCE PARAMETERS LOOKED AT IN TERMS OF WHETHER A TRACER WITHIN USED IN NEUROSCIENCE INDICATION. WHAT HE HAD PHARMACOLOGY, NON-SPECIFIC BINDING. PHYSICAL CHEMICAL PROPERTIES ABOUT AGAINST THE PARAMETERS ARE A LIST OF CRITERIA. I OWN GO THROUGH THEM ALL BUT THEY GET A SCORE. WE COME WITHOUT A MULTI-PARAMETER OPTIMIZATION SCORE AND DECIDE WHETHER A COMPOUND IS WORTH THE EFFORT AND THE TIME TO DEVELOP A NOVEL TRACER. CURRENTLY WE EXPAND THE FOCUS, WE CAN LOOK AT LABEL BODIES NANOPARTICLES ENGINEERED PROTEIN, THE PEPTIDES, THERE'S INCREASE EFFORT IN DISCOVERY FOR NEW TARGETS AND WITH THE NEW TARGETS COME NEW SETS OF LIBRARIES NOVEL COMPOUNDS, SO MANY COMPOUNDS ARE EXCITING TO RADIO LABELING SO I GET EXCITED BUT AT PFIZER TIME IS THE ESSENCE, IT HAS TO BE FIT FOR PURPOSE. WE'RE NOT JUST GOING TO TAKE A NOVEL TRACER ALONG, IF THERE'S ONE THAT'S ALREADY OUT THERE. SO WHAT'S THE NATURE OF PRIMARY TARGETS EARLY WORK FOCUSED ON RECEPTORS AND TRANSPORTER, ENZYMES ARE BECOMING A HOT TARGET. ION CHANNELS IN THE CNS IN THE PERIPHERY. OBVIOUSLY MEASUREMENT OF CELLULAR PROCESSES BESIDES GLUCOSE ME TAB RICH HIM SO WE'RE GOING TO CELL PROLIVE NATION HYPOXIA, INCREASED FOCUS ON AGONIST, PARTIAL AGONIST AND MEASUREMENT OF ENDOGENOUS LIGAND RELEASES BEYOND JUST DOPAMINE BUT INDUSTRY IN THIS CASE MAYBE UNIQUE IN THAT WE'RE LOOKING AT BETWEEN NOVEL TARGETS AND MANY UNKNOWNS, THERE'S NOT MUCH LITERATURE OUT THERE SOMETIMES SO WE DOPE KNOW SOMETIMES FOR INSTANCE B MAX MAYBE MISSING. SO WE HAVE SOME ON OUR OWN. THE FIRST BEING RECEPTOR OCCUPANCY STUDY, A BASELINE TRACE FOLLOWED BY BLOCKING STUDY, AND THIS IS THE BREAD AND BUTTER OF NEUROSCIENCE, A TYPICAL RO VERSUS PLASMA EXPOSURE CURVE AND OTHER THERAPEUTIC AREA AS WE SPEAK BUT IT HELPS TO PRIORITIZE IN THE CLINIC. YOU CAN DEFINE OCCUPANCY YOU NEED FOR EFFICACY, YOU CAN DO TIME ON TARGET STUDY THES, A WEALTH OF INFORMATION, OPTIMIZE DOSE SELECTION, SAFETY MARGIN, THAT'S ONE OF THEM. CASE 2 IS PRE-CLINICAL PET IMAGING ASSESSING MECHANISM AND THERAPEUTIC EFFICACY. WE DO THIS WITH EXTERNAL PARTNERS BUT THIS SHOW AS XENOGRAPH MICE STUDY WITH TUMOR ON THE LEFT FLANK WITH THE ARRIERO POINTED TO IT. I DON'T KNOW IF YOU CAN SEE IT. YOU LOOK AT SEVEN DAY IMAGING STUDY FOLLOWED BY A THERAPY WITH 50 MGs PER KG, CNET ALC INHIBITOR. YOU CAN SEE REDUCTION FLT AND FDG AND YOU CAN MONITOR AND MAKE SURE YOU'RE ON MECHANISM PRE-CLINICALLY. PAGE 3 EXTENDS OUT TOWARDS THE CLINIC SO YOU CAN ACCESS -- ASSESS MECHANISM IN THE EFFICACY IN THE CLINIC. SO AGAIN, PRE-TREATMENT FLG PET ON THE TOP OR YOU CAN SEE THE NON-SMALL CELL LUNG CANCER LESIONS IN THE LUNG HOPEFULLY CIRCLED IN RED THERE, AND FOUR WEEKS AFTER TREATMENT. YOU CAN SEE DIMINISHED AMOUNT. THIS IS CASE FOUR. THIS IS AN INTERESTING CASE WHERE YOU LOOK AT PET IMAGING IN THE CLINIC BUT PRAYER TO BIG PHASE 2 STUDIES. A QUICK PROOF OF MECHANISM IN A SMALL COHORT. FEG AND FLT PET SCANS IN LYMPHOMA COHORT. YOU DOSE IT WITH CDK 4 INHIBITOR , AND YOU CAN SEE THE POST FLT, MINUS 44 AND POST FTG ALSO. THIS IS CONFIRMED THROUGH HISTOCHEMISTRY STAINING WITH KI 67 MRB. WE TALKED HOW PHASE 2 IS A BIG SPOT FOR ATTRITION AND ALSO COSTLY SO YOU WANT TO KNOW BEFORE 100 OR 200 PEOPLE IN THE TRIAL WHETHER OR NOT YOUR INHIBITOR L WILL WORK BEFORE YOU SPEND UPWARDS OF $200 MILLION ON A TRIAL. YOU WOULD LIKE TO DO THIS LITTLE COHORT OF IN THIS CASE 17 WITH 15 SHOWING GREATER THAN 25 PERCENT REDUCTION OF FLT SO YOU HAVE A VERY GOOD IDEA YOUR PROOF OF CONCEPT THAT YOU KNOW WE'RE GOING BY CDK 4 INHI BIG PATHWAY IN THIS CASE. HOW DOES THIS WORK? DRUG CANDIDATE TIME LINE IS LINED UP, IT'S TARGET IDENTIFICATION, VALIDATION, LEAD OPTIMIZATION, PRE-CLINICAL DEVELOPMENT PHASE 1 STUDY, WHERE DOES PET IMMANNING COME IN? PHASE 1 STUDY IF NOT BEFOREHAND SO WE WORK OUR WAY BACK AND WHAT WE SEE IS VALIDATION HAS TO BE DONE BEFORE PET STUDY AND YOU WOULD RATHER HAVE THE NOVEL TRACERS EXISTING BEFORE THIS SO YOU CAN LOOK AT PRE-CLINICAL PET STUDIES. SO THIS WAY YOU CAN LOOK, CONFIRM TARGET ENGAGEMENT, SELECT THE CLINICAL CANDIDATE THAT YOU WILL LIKE, DOSE SELECTION FOR FIH SO ALL THIS HAS TO BE DONE, IN TANDEM WITH DRUG KENNEDY TIME LINE, SO PET AND DRUG CANDIDATE HAS TO MESH NICELY. AS THIS WORK IN EVOLVING NATURE OF PET IMMANAGING WITHIN INDUSTRY, DEVELOPING TOURS HE CAN TERM EARLY ON IT WAS PET SPECK TRACER ACADEMIC INSTITUTIONS FUND BY GOVERNMENT, TOOK IT INTERNALLY, WE GENERATED OUR OWN TRACERS AND CYCLE TONS BUT NOW CURRENTLY IT'S AN ACADEMIC INDUSTRY COLLABORATION PFIZER IS USING AND OTHER BIG PHARMA ARE GOING TOWARDS. AND POOR STRATEGIC ALLIANCES TO MITIGATE RISK AND RESOURCES. RECENTLY OBVIOUSLY THERE'S BEEN MORE FUNDING IN TERMS OF CONSORTIUM AVAILABLE FOR THIS COLLABORATION. THESE CONSORTIUM CONTINUES TO SET STANDARDS FOR IMAGING, FREE FLOWING OF IDEAS IN TERMS OF PRE-CLINICAL MOSTLY MODELS AN PFIZER BELONGS TO A NUMBER OF THEM. SO SOME OF THE CURRENT CHALLENGES FOR PFIZER AND IN TERMS OF MOLECULAR IMAGING SPECIFICALLY PET, NUMBER ONE IS EDUCATION INTERNALLY, RESEARCH TEAMS TO TELL THEM TO SHOW THEM WHICH TARGET SELECTIONS ARE IMAGEABLE AND TELL THEM THE EFFORT INVOLVED IN TASER DEVELOPMENT AND HOW THEY UTILIZE THEM. SECONDLY IS EDUCATION TOWARDS QUALITY ASSURANCE AN REGULATORY TO GET THEM UP TO SPEED ON PETARASSERS THE IND EXPLORATORY INDs AND NEXT WOULD BE TIMING. ALIGN. OF RESOURCES HAS TO COME TOGETHER. YOU CAN'T HAVE A PROGRAM THAT'S ENTERING A PHASE 2 AND THEY WANT A NOVEL TRACER, IT COSTS TIME AND WASTES TIME IF YOU'RE NOT IN ALIGNMENT. COST, METHOD VALIDATIONS, OBVIOUSLY EXTERNAL CRAB RATION OVERSIGHT IN TERMS OF RADIO TRACER PRODUCTION IN SAFE STERILE ENVIRONMENT IS IMPORTANT. YOU'RE TALKING SAFETY PACKAGES. WE WERE TALKING EARLIER AT LUNCH WHERE IF WE'RE DOING EXTERNALLY WE MAY HAVE SAFETY PACKAGES COMING FROM DIFFERENT SECTIONS. WE MAY DO THE CHEMISTRY OF THE PRE-CURSOR BUT NOW YOU HAVE AN EXTERNAL PARTNER MANUFACTURING. TO PUT TOGETHER FORM AN IND, BUT IT HAS TO HAVE THE RIGHT MANAGEMENT TO IT SO THE KEY TO IDENTIFY PFIZER AND MAINTAIN RELIABLE EXTERM PARTNERSHIPS GOING FORE AT REASONABLE COST. FUTURE OF DRUG DEVELOPMENT AT PFIZER IS STRONG. WE'RE EMBEDDED IN A LOT OF RESEARCH AREAS PRE-CLINICALLY WE USE AS POWERFUL PRE-CLINICAL TOOL FOR SCREENING COMPOUNDS, CLINICALLY, I SHOWED YOU A COUPLE OF EXAMPLES IN TERMS OF TARGET ENGAGEMENT STUDIES RECEPTOR OCCUPANCY STUDIES, PATIENT STRATIFICATION, IT IS GROWING IN TERMS OF ONCOLOGY AND DIFFERENTIATION AMONG AVAILABLE TREATMENTS. DIAGNOSIS, SO INCORPORATING IMAGING ASPECTS TO ALL THE DIFFERENT STAGES OF THE DEVELOPMENT OF DRUGS AT PFIZER IS CONTINUING STRONG. ROLE OF NIBIB CONTINUING PROBE DEVELOPMENT, TALKED ABOUT SAVING TIME MONEY AN EFFORT VALIDATING NOVEL TRACERS AN IMAGEABLE TARGETS AND WE TALKED ABOUT COST BEFORE, IT TYPICALLY COSTS PFIZER WHEN I SCOPE OUT WORKS -- WORK PLANS FOR DIFFERENT HE CAN TERM COLLABORATIVES, A MILLION DOLLARS FOR A NOVEL TRACER AND ABOUT 6 TO 12 MONTHS OF TIME, THAT'S THE PRECURSOR CHEMISTRY AND WE HAVE THE PRECURSOR, SOME ARE NOT -- BUCK TALKING A YEAR TO MAKE THE PRECURSOR. ANYTHING WE CAN DO IN TERMS TO HAVE THAT FOR TIME AN MONEY ARE KEY. TYPICALLY WE HAVE TARGETS ONE OF THREE IMAGEABLE WITH PET. SOME BECAUSE OF BACKGROUNDS LOCATION BECOME UNIMAGABLE. NEXT IS PRE-CURSOR DEVELOPMENT, NOVEL CHEMISTRY, REGULATORY AN SAFETY CLARITY, AND CONTINUE TO FOSTER COLLABORATIONS BETWEEN INDUSTRY AND ACADEMICS THROW THE GRANTS AND SUPPORT COMMUNITY SETTING UP IN TERMS OF THE MULTIPLE CONSORTIA OUT THERE. SUPPORT THE -- CONTINUE SUPPORT OF THE EDUCATION THROUGH POST-DOCTORAL TRAINING. ESPECIALLY THOSE COLLABORATIVE IN NATURE. I WOULD LIKE TO CONCLUDE AND HANK THE LEADERSHIP AT PFIZER, TIM MCCARTHY AND RIKKI WATER HOW, HE WAS ASKED TO GIVE THE TALK AND I POPPED IN FOR HER TO DO IT. I THANKS THE NEBIB FOR INVITING US AND TO ALL YOU FOR YOUR ATTENTION. [APPLAUSE] >> THE THIRD SPEAKER FOR THE SESSION IS DR. GILLES TAMAGNAN. I PRACTICE HIS NAME. THE TITLE OF HIS TALK IS USE OF EXPOSURE IND FOR EARLY PHASE CLINICAL TRIALS USINGING PET OR SPECK IMAGING. >> THANK YOU SO MUCH, CHRISTINA. THANKS, ANTONIO FOR INVITING ME AND I KNOW IT CAN BE TRICKY. SO I WANT TO TELL YOU ALL WE BRING COMPOUND FORM TO HUMAN USE USING THE EXPLORETORY IND MECHANISM, Z YOU MIGHT BE AWARE A FEW YEARS AGO, BETWEEN 2006, THE FDA ISSUED A GUIDANCE ABOUT EXPERT INDs, HA FOR US IN OUR GROUP HAS BEEN A GAME CHANGER. AND BECAUSE IT ALLOWS TO BRING COMPOUNDS IN MEN A LITTLE BIT QUICKER THAN IT WAS DONE BEFORE. AND MORE IMPORTANTLY, OTHERS TO FEW COMPOUND IN THE SAME IND SIMILAR SUBJECT TO TRY TO IDENTIFY THE BEST COMPOUND I'M GOING TO GIVE AN EXAMPLE OF THE STRATEGY. THIS SLIDE IS PRETTY COMMON TO MANY OF YOU. WE START FROM CHEMISTRY AND MEDICINAL CHEMISTRY MODEL, PRE-CLINICAL MODEL WE DO SOME IN RETRO BIND, ALL THE WORK IS -- WE DO ALL THE WORK ON (INDISCERNIBLE) NON-HUMAN PRIMATE. THE GOAL IS TO GO INTO MEN, THIS YELLOW SECTION -- SO (INAUDIBLE) AS QUICKLY AS POSSIBLE. WHILE INTRODUCING THE HUMANS TO THIS SO INITIALLY TO TEST THE COMPOUND WE HAVE IDENTIFIED B SECTION AND USE IN LARGE OR SMALL CLINICAL TRIAL, AND I'M NOT GOING TO DISCUSS HERE BUT THAT IS TO FOLLOW-UP ON WHAT DR. FREY OR MATHIS SAID ABOUT AMYLOID (INDISCERNIBLE). I'M GOING TO TALK TO YOU MOSTLY HERE. SO BEFORE WHEN SOME OF THE WORK WE'RE DOING I WANT TO ACKNOWLEDGE MANY OF THE PEOPLE, AND IT'S OBVIOUS THAT WE ASK WE NEED A GOOD CHEMISTRY TEAM AND GOOD -- THAT IS PRETTY MUCH EVERY CENTER OF THAT IN ONE WAY OR ANOTHER. BUT WHAT IS VERY, VERY CRITICAL, ALSO IS TO ASK THAT PEOPLE DO NOT MENTION VERY OFTEN, ANYONE? SO LIKE I WAS SAYING BESIDES CHEMISTRY CLINICAL IMAGING AN -- WE NEED A VERY STRONG TEAM OPERATION BECAUSE (INAUDIBLE) TASK ISSUE. ALSO THAT GOES WITH DATA MANAGEMENT AND (INAUDIBLE) WHAT KEVIN WAS SAYING EARLIER. BUT IT IS A TEAM, A STRONG TEAM FROM REGULATORY POINT OF VIEW, CALL ASSURANCE POINT OF VIEW. QUALITY L ASSURANCE NOT ONLY FROM CLINIC BUT ALSO CHEMISTRY. YOU KNOW WE TRY TO SEPARATE EVERYTHING HERE BUT AL THIS TEAM WORK ALL THE GROUP WORK AS ONE TEAM, SO I'M GOING TO GIVE YOU ONE QUICK EXAMPLE ON (INAUDIBLE) WHICH IS A PET TRACER FOR THE TARGET WHICH IS (INDISCERNIBLE) P PD-10 IS (INAUDIBLE) PHARMACEUTICAL COMPANY FOR NEUROGENERAL TECH DISORDERS. SO THE WORK I'M GOING TO INSTRUCT TO YOU HAS BEEN DONE IN 18 MONTHS FROM THIS SLIDE HERE SO YOU CAN IMAGINE 8 MONTHS AGO WE MADE THIS -- THE TWO COMPONENTS, BINDING AWE SAY, FROM THE BINDING WE SAW IT WAS MOVING TO A MONKEY. THE MONKEY, WE HAVE (INAUDIBLE) OF 659 THE DIFFERENCE BETWEEN 654 AND 659 WAS THE BINDING AFFINITY, BOTH WERE VERY, VERY CLOSE TO EACH OTHER. THEY WERE SELECTIVE TO (INAUDIBLE) SO WE DIDN'T KNOW FROM THE BINDING FROM THE IMAGE WHICH ONE TO (INAUDIBLE) SO WE FELL THE NEED TO GO WITH BOTH. LIKE IN ALL -- SAMPLING. AND THAT IS GOING TO BE USED FOR MODALITIES. FOR EACH MONKEY WE HAVE MR T-1 WEIGHED. WE USE (INAUDIBLE) PET IMAGING. ALL THIS WORK WAS DONE WITH COLLABORATOR (INAUDIBLE). AND THEN PET IMAGES TO THE -- THE CURVE FORMS VOI ON MI AND LOOK AT THE CALCULATED THE BINDING POTENTIAL AND WE PERFORMED AN OCCUPANCY STUDY TO SHOW SELECTIVITY. SO BASICALLY WHAT YOU SEE, THE TWO COMPOUNDS, ON THE LEFT, VERY THROUGH WASH OUT FORWARD FOR (INAUDIBLE) MUCH FASTER UPTAKE BUT MUCH FASTER BLOCK OUT. WE DID A SELECTIVE TRACER AND WITH WE SEE WE GOT IT FOR EITHER COMPONENT VERY WELL. WHAT RESEEING, (INAUDIBLE) 9 THE SIGNAL WAS SELECTIVE IN REGION OF PD-10. THAT WAS THE MAIN ISSUE. IF YOU WANT A PICTURE WHICH I DON'T BELIEVE -- THE -- (INAUDIBLE) IF YOU DO A -- MP-10 YOU GET ALMOST NOTHING AND LOWER DOSE PK-10 YOU GET (INAUDIBLE) SIGNAL COMPLETELY WITH (INDISCERNIBLE) THAT IS WHAT YOU CAN SEE WHEN YOU DO A CLOSE DOSE ON PANSY. SO FROM THOSE TUMOR CASE STUDIES, NEURON TWO OR THREE, 20 UNCHANGE MONKEY STUDIES, WE SAID WE HAVE A COMPOUND, WE HAVE TWO COMPOUNDS WHO LOOKS GOOD IN MONKEY, WHICH ARE WE GOING TO MOVE TO HUMAN. THE FASTER KINETIC WOULD BE THE BEST ONE TO MOVE FORWARD. BUT TALKING TO SOME IN THE INDUSTRY, INFORMATION WAS GIVEN TO ME, INFORMATION WAS FOLLOWING. PD 10 DENSITY IN MEN IS GOING TO BE LOWER THAN IN MONKEY, AND PD 10 (INAUDIBLE) IS SEMITO MONKEY. IF IT WAS LOWER IN MEN THAN MONKEY WHAT YOU WANT TO IS A COMPOUND WITH SLOW KINETIC MONKEY BECAUSE TO BE MUCH FASTst FATHER -- SENSED DON'T KNOW WHICH IS CORRECT WE'LL BRING THE TWO (INAUDIBLE). FOR THAT WE DID VALIDATION WITH CMC TWO COMPOUNDS, WE ACQUIRED ONLY ONE OF TWO OPT STRUCTURE OF THE TWO COMPOUNDS IS VERY SIMILAR. AS YOU CAN SEE. BASICALLY WE -- ONE IND WITH TWO COMPOUND, ONE SET OF CLINICAL PROTOCOL, ALL THE DATA CONNECTED FROM THE MONKEY STUDIES. AND WE (INAUDIBLE) UNDER STUDY BEFORE DO GOING THERE THE STUDY WAS TO INJECT TWO COMPOUNDS IN HUMAN SUBJECTS TO DO A TEST AND DOSIMETRY, WE SUGGEST DOSIMETRY AT THE END IS SO MY KNOWLEDGE I HAVE NEVER SEEN COMPOUND DYING BECAUSE DOSIMETRY WAS BAD BUT TEST CAN BE THE CRITICAL STEP HERE SO WE TEST RETEST IF IT'S GOOD WE GO TO TOE SYMMETRY, IF IT IS NOT GOOD WE MOVE TO THE NEXT COMPOUND. SO HUMANS STUDIES FOR THAT YOU NEED GMP DATA WE HAVE ON SITE. YOU NEED TO HAVE CLINICAL TRIAL PLANNING AND CONDUCT OF THE STUDY SO YOU NEED -- YOU NODE TO REYOU THE SUBJECT IT IS BETTER, THIS IS RESEARCH YOU NEED (INAUDIBLE) AND IF I HAVE TIME I'LL TELL YOU WHY. IMAGE POSSESSING IN REGARD TO (INAUDIBLE) I SPOKE ABOUT IT AND REGULATORY GROUP IS TO DEAL WITH FDA ON THE IRB. MANAGEMENT TO CHECK ALL THE DATA AND TUMORS IN A GOOD WAY. SO THE FIRST STUDY WE DID WE DECIDED TO DO TWO COMPOUNDS SO WE SUBMITTED APPLICATIONS 30 DAYS LATER THE FDA SAID YOU CAN PROCEED. WE HAD QUESTIONING IN BETWEEN BUT THE FDA SAID YOU CAN PROCEED. AND WE WEAPON FOR TEST RETEST (INAUDIBLE) WE TOOK THE MI FROM EACH SUBJECT, WE USE THE HR (INAUDIBLE) CAMERA, ON ALL SUBJECT WE TOOK RANDOM SAMPLING, WE LOOK AT FIVE HC CONTROL TO (INDISCERNIBLE) CONTROL FOR THE MOST DOSE. WE LOOK AT 2 AS CONTROL AND (INAUDIBLE) I STOP AT TWO SUBJECTS OR YOU WILL SEE WHY SOON. SO THE DATA, IMAGING WHERE MOTION CORRECTED, STARTS WITH ME. (INAUDIBLE) INSTITUTE SPACE, (INAUDIBLE) FROM VIEWER TEMPLATE. WE USE THE PLASMA FOR CORRECTION OF THE IMAGES BECAUSE THAT'S THE QUESTION WE IMMEDIATED TO ASK. IT WAS CALCULATED FOR 2T (INAUDIBLE) AND CALCULATED USING (INAUDIBLE) SO WE MEASURED FOR SIX HOURS, THE -- YOU CAN SEE NICE YOU CAN TAKE (INAUDIBLE) BREAK 19 MINUTING AND SO ON. YOU CAN SEE LIKE THE MONKEY, THE WERE OUT IS SLOW FOR THE NEXT 6, 5, 4. ONE 659 WE MEASURE THREE AND A HALF HOURS UPTAKE WAS MUCH FASTER THAN 654 SIMILAR TO WHAT WE HAVE SEEN IN MONKEY. SO WE CALCULATED THE TEST RETEST FOR THE TWO COMPONENTS. (INAUDIBLE) TEST RETEST FOR ONE SUBJECT OF 45%, SUBJECT 55%. TWO SUBJECT WE DROPPED AND FOCUS OUR ATTENTION (INDISCERNIBLE) YOU CAN SEE -- THE TEST RETEST WHEN YOU HAVE 90 MINUTES OF SCANNING DEPENDING ON THE REGION IS BETWEEN 5 TO 8%. WE GOT TO WHERE WE SATISFIED THIS COMPONENT, WE SAID NOW IT'S READY FOR PRIME TIME. WE DID A DOSE SYMMETRY STUDY AN BASICALLY IT IS GOOD TO EVALUATE IN POPULATION. SO THAT WAS AVAILABLE AND WE DECIDED MAYBE SOME OF YOU ARE AWARE PD 810, TO LOOK AT IT IN THESE SUBJECTS, ALMOST TEN YEARS AGO, PRESENTED SOME WORK FROM (INAUDIBLE), TRANSGENIC MICE SHOWING DECREASE PD-10 MICE WITH (INAUDIBLE) GENE. SO THAT WAS REASON FOR US TO LOOK AT (INAUDIBLE) SO WE INITIATED A STUDY IN (INDISCERNIBLE). WE MIGHT HAVE A COUPLE MORE SUBJECTS. BASICALLY WE LOOK AT THE SUBJECTS YOU CAN SEE THE POPULATION IS BETWEEN LATE 20s TO EARLY 70s. ITf 60s. (INDISCERNIBLE) THINGS ON THE -- THAT MAKES A LOT OF SENSE BECAUSE IT IS A GENETIC DISEASE SO EVERYBODY, HAVE THIS MUTATION TO DEVELOP THE DISEASE AND PEOPLE ARE GOING TO DEVELOP IT IN TIME. SO FIRST THING FIRST WAS TO COMPARE THE BINDING POTENTIAL OF THIS ENZYME IN CONTROL ON WHAT WE CAN SEE, MANY RECEPTORS WHERE WE DECREASE PD 10. SO WE HAVE INCREASE IN NUMBER, STILL CORRECT WHICH MEAN THAT WHEN YOU WANT TO COMPARE SUBJECTS TO LC CONTROL YOU NEED TO SAME GROUP HERE. SO AS I TOLD YOU, IT'S A GENETIC DISEASE. WHAT WE'RE LOOKING AT IS CGA REPEAT SO BASICALLY EVERYBODY WITH CGA REPEAT ABOVE 35 IS DIAGNOSED AS POTENTIALLY DEVELOPING (INDISCERNIBLE) SO ALL THE SUBJECT WE HAVE LOOKED AT ALMOST ALL OF THEM, REPEAT AROUND 40 EXCEPT THIS ONE WHETHER CGA REPEAT OF 68. THE (INAUDIBLE) IN THE MID 40s. WHAT IS CRITICAL IS THE -- WHAT PATHOLOGISTS CALL, THAT V SCORE IS THE CGA REPEAT MINUS 35.5, THE SCORE IS MOST SEVERE DEPENDS (INAUDIBLE). WE LOOK AT THE MOTOR SCORE ON THE OTHER SCORE. FOR THE (INDISCERNIBLE) THE AGE IS AROUND 52 YEARS OLD. THAT IS WHAT WOULD BE EXPECTED. ON THE -- ALSO CLOSE TO 50. BASICALLY THAT IS DIFFERENT, AROUND 40 TO 58 FOR ANYTHING FOR THE MANIFEST, THE SAME THING. SO ON. IMAGINES, IT SHOULD BE COMPARABLE, THAT IS 30 YEARS OLD MALE CONTROL, YOU CAN SEE MR, PET, YOU CAN SEE A VERY NICE UPTAKE IN -- SUBJECT FEMALE WITH (INAUDIBLE) 310 YOU CAN SEE HERE A NICE PG 10 ACTIVATION IN THE (INDISCERNIBLE). SOMEONE WITH WITH 4.2 IS EVEN MORE NOISE AS YOU CAN SEE ON THIS IMAGE. BUT ONE MORE THING TO LOOK AT IMAGES ON THE GRAPH, WHAT WE SEE IS A VERY NICE CORRELATION BETWEEN THE UPTAKE OF (INAUDIBLE) AND (INAUDIBLE) WHAT IS VERY STRIKING, THIS SUBJECT HERE WAS PATHOLOGY OF 658 I THINK. ACTUALLY WE COULD NOT SEE, WE CANNOT VISUALIZE ANYTHING IN THE BRANCH, IT WAS ABSOLUTELY PRETTY (INAUDIBLE). FINALLY SAW A CORRELATION BETWEEN UPTAKE TO (INAUDIBLE). THAT IS ANOTHER WAY TO LOOK AT THIS SO BASICALLY YOU HAVE NO MORE SUBJECTS (INAUDIBLE). AS YOU HAVE SEEN, AS WE SEEK -- DISEASE MR DISEASE, OF TO KIND OF EXCEPT AT ONE POINT ALL L ARE GOING TO GO DOWN AS THE SAME UPTAKE OR SAME BINDING POTENTIAL THAN THE NORMAL CONTROL. (INDISCERNIBLE) SCALE. SO THE CONCLUSION HERE, WE HAVE SHOWN THAT THERE IS A (INDISCERNIBLE) WHICH CORRELATE WITH SEVERITY AND PATHOLOGY. EXPECTED WITH THE PATHOLOGY OF (INDISCERNIBLE) EARLY IN THE DISEASE, SMALL SAMPLE SIZE, WE NEED TO HAVE A BETTER MATCH BETWEEN AGE AND GENTER. THAT WAS IN THE -- FROM THE TIME WE IDENTIFIED THE COMPONENT FROM MEDICINAL CHEMISTRY BENCH, BINDING ASSAY, TO WHAT I HAVE SHOWN HERE, JUST ABOVE 18 MONTHS, SO WHAT YOU CAN DO WHEN YOU HAVE A TEAM THE WAY I PRESENT IT TO YOU. I DIDN'T COST $10 MILLION, THAT WAS A GOOD PART OF THE IT. WHAT WE ARE DOING NOW IS LOOK AT THIS POPULATION WITH OTHER RECEPTOR, OTHER COMPOUNDS FOR SELECTIVE RECEPTOR, EXPLORATORY IND. SO SINCE WE HAVE DONE THE STUDY WE CLOSED TO EXPLORATORY IND TO OPEN THE FULL IND, WE SUBMITTED THE IND WE DID NOT HAVE ANY HUMAN DATA TO PRESENT. SO KELLY, THE V SECTION IS A SECTION THAT OF HUMAN EXPERIENCE WAS NOT TERRIBLE BUT WHEN WE CLOSE (INAUDIBLE) WE DESCRIBE ALL THE DATA WE REQUIRE. SO WE MIGHT HAVE FIVE MINUTES SO I'LL SHOW YOU ANOTHER COMPOUND. I SUSPECT (INDISCERNIBLE) THAT IS I'M GOING TO YOU THESE EXAMPLES. I'M GOING TO SHOW YOU EXAMPLE, BECAUSE I MENTION EARLIER IT'S GOOD TO HAVE IN PERSON FACILITY, -- ALL PROGRAMS COME FROM (INAUDIBLE). SINCE THEN WE -- FOR PEOPLE (INAUDIBLE) (INDISCERNIBLE) IT WAS A COMPONENT TO MERCK TO PHASE 3 CLINICAL TRIALS AND IT WAS DROPPED TWO, THREE MONTHS AGO. (INDISCERNIBLE) NIGH UPTAKE IN STRIATUM AS YOU EXPECT TO SEE. WE DID DOSE OCCUPANCY USING (INAUDIBLE) WE MADE ON ALL. WE TEST MONKEY AND ALL THE WORK THAT NEEDS TO BE DONE. FROM THIS WORK WE SAID THIS IS INTERESTING WE'RE GOING TO BRING INTO MEN. WE DEVELOP A 2A COUPON WAS NOT TO DO DOSE OCCUPANCY STUDIES FROM THE FARM SUECAL COMPANY BUT TO LOOK ATÖ SUBJECTS IN BECAUSE IN PIR KIN SON DISEASE YOU EXPECT TO SEE (INAUDIBLE). WE MOVE THIS IMMA'AM, NICE UPTAKE IN VIE YEAH TOM. -- STRIATUM. NOW I'LL SHOW YOU SUBJECT NUMBER 1, THIS IS PROBABLY SUBJECT NUMBER 26789 NUMBER 1 AND NUMBER 2. CLINICAL PROTOCOL, PEOPLE>)H– RECRUITING (INDISCERNIBLE) SCREEN SIGNED CONSENT FORM, (INDISCERNIBLE) THERE WAS SUPPOSED TO COME A WEEK LATER TO GET A SCAN, A BATTERY OF THINGS YOU SHOULD NOT DO, GOING BACK UP. THEY WERE COMING OPPOSITE ONLY THE MORN OF THE SCALE. THE TEST, WE TEST (INAUDIBLE) FOR THE SUBJECTS, NO PROBLEM. TEST RETEST FOR SUBJECT NUMBER 2, THAT WAS FINE. SO 5% RANGE. WE DO SUBJECT NUMBER 3, WE DO THE TEST, I'M NOT GOING TO SHOW IT TO YOU RIGHT NOW AND HE COMES BACK A WEEK OR SO. I'M GOING TO TALK ABOUT THIS LATER ON SO SUBJECT 1, 2 AND SUBJECT 4, YOU CAN SEE THE TEST RETEST BETWEEN THE DIFFERENT SUBJECT WHAT YOU'RE USING FOR MODELING IS 0.10%. SO SUBJECT NUMBER ONE, NUMBER 3 COME, VERY HAPPY, COME A WEEK LATER. I KNOW -- THERE WAS PANIC ON BOARD BECAUSE FIRST QUESTION IS DID WE MIX THE WRONG COMPOUND. THAT IS MOST OF THE GMP (INAUDIBLE) FACILE. SO WE INVESTIGATED AND COMPONENT WAS RIGHT. WE WANT TO SEE IF THE CAMERA WAS BROKEN. CAMERA WAS FINE, THEN WE SAW THAT SOFTWARE WAS SOMETHING WAS WRONG WITH THE SOFTWARE. FINALLY SOMEONE SAID DOES THIS PERSON OR LADY TAKE DRUGS? EVEN IF WE GO THROUGH BLOOD WE DIP SEE ANYTHING SO WE CALLED HER, NO, SHE WAS -- NO, NOTHING. THE DAY AFTER SHE CALLED US SAYING BY THE WAY ON MY WAY TO YOUR FACILITY I STOP BY DUNCAN DONUTSES AND I GOT A (INAUDIBLE). THAT IS ONE HOUR BEFORE THE SCAN. SO WE HAD DONE EVERYTHING RIGHT AND WITHOUT KNOWING DOSE OCCUPANCY STUDY SO WE SHOW THE SPECIFICITY OF THIS TRACER. SO THAT'S BASICALLY -- IT'S WHY NOW EVERY TIME DWOA COMPOUND FOR THE FIST TIME, THE SUBJECT HAS TO SLEEP IN IN PATIENT FACILITY, THAT WE SMALL CALL OR NOT SO WE HAVE FULL CONTROL OF WHETHER WE'RE DOING. I TRY TO TELL YOU YOU CAN GO QUICKLY MODEL TO CLINICAL STUDY USING THE EXPERT IND. WE HAVE TO GIVE CREDIT TO THE FDA TO DEVELOP THIS PROGRAM. MY FEELING IS NOT ENOUGH PEOPLE ARE USING THIS PROGRAM TO BRING COMPANY TO MEN. WITH WE HAVE DONE CLOSE TO 40 HE CAN EMPLOYERTORY INDs, IT'S MECHANISM WHICH WORKS VERY WELL, VERY -- TO MAKE SURE WE CAN DO THESE KINDS OF OPPORTUNITIES. AGAIN CLEARLY THERE IS ONE ASPECT WE CANNOT -- WE HAVE TO BE VERY CAREFUL OF, IT'S THE SAFE THE OF THE SUBJECT THAT MEANS THAT THIS -- THE PROJECT IS -- THE CMC EXPLORATORY IND IS ASSEMBLED FOR (INAUDIBLE). I THINK THAT'S IT. [APPLAUSE] >> IF I STILL HAVE ONE MINUTE, THE WORK I HAVE SHOWN YOU IS WORK WE DO IN -- A PROJECT WE DECIDED TO DO IN HOUSE FROM BEGINNING TO END. ALSO I HAVE WORKED SOME OF E I DON'T THINK HE'S HERE BUT SOME COLLEAGUES HERE IN THE U.S. WHERE THEY DIDN'T HAVE RESOURCES TO BRING A COMPONENT TO MEN IT WAS BASICALLY A COLLABORATION WHERE ALL CHEMISTRY WORK WAS IN THIS BOTTLENECK OF BRINGING COMPANY TO MEN USING EXPLORATORY IND IS WHAT I DID. SO I DID IT ONCE IN THE U.S., I TALKED WITH SOMEONE ELSE TO DO IT AGAIN IN THE U.S. BUT MORE PERFORMLY, WHICH IS VERY BIZARRE TO ME, WE ARE A U.S. GROUP HERE, I WORK A LOT WITH JAPANESE GROUP OF FOLKS SO I KNOW EARLIER WE WERE TALKING THIS MORNING ABOUT ALL THE DIFFICULTY TO BRING THE COMPANY TO MEN. WHEN YOU HAVE THE STRUCTURE TO DO IT IT'S IN THE THAT DIFFICULT. YOU SHOULDN'T BE AFRAID OF ASKING AROUND IF YOU NEED IT./Zh >> THANK YOU VERY MUCH. SO WE'LL NOW HAVE A BREAK. PLEASE DO COME BACK AT 2: 406789 WE'RE GOING TO START THE NEXT SESSION PROMPT. THANK YOU. >> WE'RE COMING TO THE FINAL PART OF OUR PROGRAM, IF PEOPLE COULD TAKE THEIR SEATS. I WOULD LIKE TO ASK SINCE OUR AFTERNOON PAM WILL INCLUDE ALL OF OUR SPEAKERS BOTH MORNING AN AFTERNOON PEOPLE IF OUR -- UNFORTUNATELY DUE TO SPACE LIMITATIONS WE WILL NOT BE HAVING SEATS IN THE FRONT FOR EVERYBODY. I'LL BE ASKING IF SPEAKERS FROM THE MORNING IF YOU WOULD LIKE TO TAKE SOME OF THE SEATS IN THE FRONT ROW THAT WE HAVE RESERVED, THAT WAY IT WILL BE POSSIBLE THE ASSEMBLE OUR PANEL PROMPTLY AT THE END OF THE LAST TALK. AT THIS IT'S ME PLEASURE TO INTRODUCE DR. DAN VIGNERON FROM US SAN FRANCISCO WHO TELL US ABOUT CLINICAL TRANSLATION OF HYPERPOLARIZED CARBON 13 MRI TECHNOLOGY SUCCESSES AND CHALLENGES. >> THANK YOU VERY MUCH, TONY AND TO ALL NIBIB FOR PUTTING TOGETHER THIS GREAT WORKSHOP OKAY. GREAT. SO THIS WAS A FAIRLY LARGE ACADEMIC INDUSTRY COLLABORATION WITH GREAT SUPPORT FROM THE NIH ESPECIALLY NEBIB, TO -- NIBIB TO DO CLINICAL TRANS RATION OF HYPERPOLARIZED CARBON 13 MRI TECHNOLOGIES. ONE ISSUE WITH MRI IS IT ITS SENSITIVITY, AT ROOM TEMPERATURES, AND THE FIELD STRENGTH, TYPICAL MRI SYSTEM, ONLY ONE OUT OF EVERY MILLION PROTONS ARE DETECTABLE. SO YOU'RE ONLY DETECTING A VERY, VERY SMALL PERCENTAGE OF THE SPINS AT PHYSIOLOGIC OR ROOM TEMPERATUREMENT AT ONE DEGREE KELVIN WE CAN GO FROM ONE OUT OF A MILLION TO EVERY ELECTRON ALIGN. SO A MILLION FOLD INCREASE OF ROUGHLY THE ELECTRON AN RELEASED IN THE PROTONS VERY LOW TEMPERATURES. THIS CAN ALSO BE TRANSFERRED TO THE CARBON. SO NOW WE'RE GETTING UP TO 100,000 FOLD INCREASE, WE CAN GET SIGNALS THAT ARE STRONGER THAN WATER. AND THIS TECHNOLOGY WAS DEVELOPED BY COMPANY MERGED WITH EMERSHAM THEN MERGED WITH GE. THE FIRST PAPER SHOWING DISILLUSION DMP WAS IN 2003. SO JUST TEN YEARS AGO THIS TECHNOLOGY WAS SHOWN TO GET OVER 10,000 FOLD, FIVE ORDERS OF MAGNITUDE INCREASE IN SIGNAL FOR CARBON NUCLEUS. SOLVE INTO A LIQUID SOLUTION WHICH CAN BE INJECTED AND DO RAPID HIGH SENSITIVITY MRI SO FIRST PAPERS WERE 2006, SO COLLEAGUES DEVELOPED THIS AS NEW HYPERPOLAR 13 ENZYMEAMIC APPROACH FOR KEY METABOLIC PATHWAYS FOR THE FIRST TIME SO THIS DATA LOOKING AT CANCER WAS SIGNIFICANT BECAUSE YOU CAN SEE THIS GO IN BE DISTRICT BUD HERE ALANINE IS HIGH IN MUSCLE AND LIVER BUT IN CANCER HIGH LEVELS LOOK AT A TIME. SO WHAT IS GOING ON HERE? THIS IS WHAT WE'RE INJECTING. HYPERPOLARIZED PYRUVATE SO IN THIS CASE CARBON NUCLEUS IS ALIGNED WITH 100,000 TIMES MORE THAN THERMAL. OOZE IT GOES THROUGH ENZYMATIC CONVERSION, THIS IS STILL ALIGN ED, AND STILL GETS SIGNAL BUT THE MOLECULAR ENVIRONMENT HAS CHANGED, THE FIELD AROUND IT HAS CHANGED SO IT'S A SLIGHTLY DIFFERENT FREQUENCY AND WE CAN DETECT THAT SO WE CAN DETECT THE CONVERGE THROUGH THE ENZYME, (INAUDIBLE) ALANINE OR TO LACTATE UP REGULATED IN CANCER BY OVER FIVE FOLD. SO THE TIME LINE, FIRST PAPER CAME OUT IN 2003 TEN YEARS AGO, ABOUT THAT TIME, THERE WAS A TALK MOLECULAR IMAGING CONFERENCE IN SAN FRANCISCO THAT I SAW. AND THEN THE AMERSHAM PROJECT LEADER AT THE TIME DISCUSSED DURING THE CLINICAL TRIAL, THERE HAD BEEN CLINICAL ADVISORY BOARDS, IT'S AN ONCOLOGIST DRIVEN CLINICAL TRIAL DESIGN, PEOPLE ASK ME WHY DID I CHOOSE PROSTATE CANCER. I DIDN'T CHOOSE IT, ECOLOGISTS CHOSE IT AND IT CHOSE ME BECAUSE MY GROUP WITH JOHN HAD BEEN DOING PROSTATE CANCER IMAGING FOR 20 YEARS. SO WE WORKED WITH THEM TO DESIGN THE SMALL STERILE COMPOUND, STERILE POE PROCEDURE RIGHT NEXT TO A BUILDING WE WERE PUTTING IN AT THE TIME T. ROADMAP INITIATIVE THAT DR. MEDEGREW TALKED THIS MORNING WAS KEY FOR US, AND FUNDED THIS INITIAL SCIENTIFIC DEVELOPMENT AND BIOENGINEERING CRITICAL FORGETTING THE STUDY GOING AND TRANSLATING IT FOR HUMANS. THE FIRST POLARIZER WAS SHIPPED IN 2006 THE SAME AS SHOWN YOU BEFORE. AND TO DO TECHNOLOGY TRANSFER WE PURCHASED A SEPARATE PRE-CLINICAL POLARIZER TO ENABLE US TO DO MORE PRE-CLINICAL STUDIES. AS THIS ONE WAS BEING CONVERTED OVER TO DOING STERILE ONES. WE GOT A RO-1 FROM NIBIB FOR SEQUENCE DEVELOPMENT FOR MRI IN COLLABORATION WITH JOHN PAUL'S GROUP STANFORD. IN 20078 WE DID THE PRE-CLINICAL TRANSGENIC PROSTATE CANCER STUFF THE DIS FOR THE FIRST TIME AND DOGS AN ADDITIONAL SAFETY STUDIES. OUR CLINICAL PHARMACY GROUP DEVELOPED THE SOPs FOR STERILE COMPOUNDING IN NEW PROOF CONCEPT POLARIZER WITH SUBSTANTIAL MODIFICATIONS BY OUR TEAM (INAUDIBLE) VALUE DATED SEQUENCES, 2009 TO 10 WE DID THE PROCESS QUALIFICATIONS AND FINAL DEVELOPMENT THE IND WEAPON IN, WE SUBMITTED MINOR CHANGE, APPROVED BY THE FDA IN 2010 IN OCTOBER WE STARTED PATIENTS JUST A FEW WEEKS LATER. AND COMPLETED OUR PHASE 1 PERSON MAN CLINICAL TRIAL 30 PATIENTS IN THE NEXT YEAR. ALSO NOW WE HAVE A CENTER GRANT WHICH IS SUPPORTING TECHNOLOGY DEVELOPMENT DISSEMINATION, ENABLE NEW STUDIES ALSO NEW PATIENT STUDIES BRAIN PROSTATE CANCER SUPPORTED BY NCI NIBIB. I'LL TALK ANT THOSE AT THE END. -- ABOUT THOSE IN THE END. IN THE DISCUSSION EARLIER SOMEONE MENTIONED IT TAKES MORE THAN JUST ONE PASSIONATE HARD-WORKING PERSON THE TAKE SOMETHING THROUGH. IN THIS CASE IT WAS MORE THAN TEN. ESPECIALLY IN THE LEADERSHIP HERE THERE WERE A LARGE NUMBER WITH GE JONATHAN MURRAY WAS THE CROSS BUSINESS LEADER WHICH IS DEALING WITH MEDICAL DIAGNOSTICS AN MR AND TECHNICAL DEVELOPMENT AT GRC. SO THEY DID A MEDICAL DIAGNOSTICS GMP VALIDATION OF THE AGENT AT UCSF SARA KNELL SEN OVERSAW THE WHOLE PROJECT AND HAD A GOOD STRATEGY OF DISTRIBUTING RESPONSIBILITY TO THE MULTI-DISCIPLINARY TEAM, SO ALL OF US WERE DUE TO DEAL WITH OUR OWN PIECES, BOTH SUCCESSES AND THE CHALLENGES. OF GETTING IT GOING. DR. MARCUS FERONI IN THE DRUG PRODUCT SERVICES LAB CLINICAL PHARMACY WHICH IS DOING GOOD UCSF OVERSAW THE PROCESS QUALIFICATION TO EXCEPTIONAL JOB, ONCOLOGY GROUP INVESTIGATIONAL THERAPEUTICS DID THE IND SUBMISSION AND IRB APPROVAL AND CLINICAL TRIAL I DON'T HAVE SIGHT, MY GROUP WORKED ON THE ENGINEERING FOR THE MRI AND DISILLUSION D NEXTP AND JOHN'S GROUP OVERSAW THE PRE-CLINICAL STUDY AND THE PATIENT MR PROTOCOLS. OUR STRATEGY WAS THINK GLOBAL ACT LOCAL CONSIDERING THE -- WE CONSIDERED THE WIDESPREAD FUTURE NEEDS AND VALUE BUT THE ACTUAL STUDIES AN METHODS WERE DRIVEN BY LOCAL INSTITUTIONAL FACILITIES EXPERTISE PATIENT POPULATION AND NEEDS AND MY MANTRA BUT NEVER GIVE UP, NEVER SURRENDER. EVERY DAY WE RAN INTO A CATCH 22. SO THE CHALLENGES WITH DEVELOPMENTS TEMPERATURE AND CONCENTRATION OF 250 MILLIMOLAR WITH HIGH POLARIZATION REMOVING THE STANDARD SOPs FOR THE PHARMACY TECHNICIANS TO ROUTINELY RUN THIS IN THE CLEAVE ROOM. THE STERILIZATION PROCEDURES WERE AN ISSUE TO DEVELOP FLOOD PATH COMPONENTS, THAT TOOK TIME AND THEN DEVELOP THE MR PIECE FOR EXPECTATION RECEPTION AND FAST 3-D VOLUME METRIC IMAGING. COMPLEX PATIENT ENROLLMENT AND CLINICAL TESTS AN MONITORING WERE ALSO CHALLENGING THAT HAD TO BE OVERCOME AND BRINGING TO DIFFERENCE HE CAN EXPERTISE REQUIRED COORDINATE THE VARIOUS DEVELOPMENT AND DEAL WITH ACADEMIC INDUSTRY AGREEMENTS AND DR. SARA NELSON DID AN OUTSTANDING JOB COORDINATING THAT ALONG WITH JONATHAN MURRAY. ESTABLISHING SAFETY AND POTENTIAL PATIENT BENEFIT PRIOR TO IRB AND FDA APPROVAL. TO LARGE NUMBER OF SAFETY STUDIES BOTH IN ANIMALS AND THEN THERE WERE SOME NORMAL VOLUNTEERS IN YOUNG AGE MATCHED DONE IN EUROPE BUT THAT WAS WITH UNPOLARIZED, JUST MADE THE ACTUAL REPe  PREPARATION BUT NOT HYPERPOLARIZED. RATS MICE TRANSGENIC MODELS K-9, STUDIES IN FINAL DOSES AND ACQUISITION METHODS, THIS ALL WENT TONE THE FDA SUBMISSION. IN OUR IRB. THIS SHOWS OUR FACILITY HERE. RIGHT NEXT TO THE THREE Ps THIS ROOM IS ME INTO A CLEAVE ROOM. THIS IS THE ORIGINAL POLARIZER IN THAT PICTURE BEFORE. YOU CAN SEE IT'S NOT SET UP FOR A STERILE PROCESSING BUT THEN WE DID THE FIRST STUDIES JUST TO MAKE SURE IT WOULD WORK IN OUR ENVIRONMENT, TECHNOLOGY TRANSFER. THESE WERE ACQUIRED IN SWEDEN, UCSF AN QUALITY WAS GOOD IF NOT BETTER WITH BEAR SCANNER IN HIGHER FIELD. AND THEN WE DID A NUMBER OF PRE-CLINICAL STUDIES, SUPPORTIVE OF ROADMAP INITIATIVE TO OBTAIN THE PRE-IND CORRELATIONS WITH TUMOR AGGRESSIVENESS IN RESPONSE TO THERAPY FOR PROSTATE CANCER AND CONDUCT THE COMBINED C-13 MR MOLECULAR BIOLOGY AND BIOCHEMICAL ASSAYS FOR BASIC CANCER RESEARCH. WE DID PRE-CLINICAL STUDIES DEVELOP AND TEST THE NEW POLARIZED INSTRUMENTATION, RATS, MICE, DOGS, CELL AND IT SHALL SHOE BIOREACTOR STUDIES AND A PRIMATE MODEL I'LL SHOW IN A MINUTE. SO THIS IS WHAT YOU GET WHEN YOU INJECT THE PYRUVATE YOU GET A HUGE SIGNAL, STRONGER THAN WATER, REALLY TREMENDOUS S AND R FOR MR I. THESE ARE EVERY THREE SECONDS SIX SECONDS AFTER INJECTION YOU SEE CONVERSION THE ALANINE IN THE ANIMAL BUT NOTICE PYRUVATE IS HIGHER THAN ANYTHING ELSE, ISN'TN'T TRUE IN CANCER LDH ACTIVITY IS UP-REGULATED SO THE WARBERG EFFECT, RAPID CONVERGENCE, MANY FOLD MORE THAN WE SEE IN NORMAL TISSUE. THESE ARE SET UP HERE SO WE USE THE CLINICAL SCANNER BUT SET UP A SMALL COIL FOR ANIMALS. BECAUSE OF THE HIGH SENSITIVETIVE CREATED EXTERNALLY, WE DON'T NEED HIGH FIELD MRI SCAN. AT LEAST NOT FOR THE C-13 IMAGING, FROM THIS PROJECT AT STANFORD WE DEVELOP A FAST READ OUT FOR 16 FOLD ACCELERATED MRSA POSITION. WE FOCUSED ON ONE IMAGING HERE, THIS IS ABOUT TEN SECONDS, BEAUCOUP TECHNOLOGY WE'RE DOWN TO 300 MILISECONDS TO DO THE SAME QUALITY BASICALLY. AND THIS PAPER, FROM (INDISCERNIBLE) GROUP IN COLLABORATION WITH US, IN PUBLISHED IN CANCER RESEARCH SHOW THE ABILITY TO DETECT IN VIVO PROSTATE CANCER MODEL AND METASTASIS, PRIMATE IN THE METASTASIS. RA'S REALLY SIGNIFICANT BUT DIFFERENCE BETWEEN NORMAL EARLY STAGE AN LATE STAGE. AND THE LATE STAGE GROUP SEPARATELY FROM THE EARLY AND THEN THE NORMAL PROSTATE, THIS IS IMPORTANT BECAUSE IN THE CLINICAL MANAGEMENT PROSTATE CANCER A LARGE NUMBER OF THESE CANCERS ARE NOT CLINICALLY SIGNATURE CAB OR WON'T METASTASIZE SO IDENTIFYING THE INDOLENT DISEASE FROM THE CLINICALLY SIGNIFICANT DISEASE IS A CURRENT UNMET CLINICAL NEED. SO THIS WAS VERY INTERESTING AND CORRELATED WITH THE GENETIC AND PROTEOMIC CHANGES THAT OCCUR WITH PROSTATE CANCER. AND THEN IN ADDITION TO THAT, A REAL SIGNIFICANT CLINICAL MANAGEMENT PROBLEM IS RESPONSE TOTHER FI -- THERAPY. SO I'M LOOKING AT THE MODEL SOME RESPONDERS SOME NON-RESPONDERS TO THE ANDROGEN DEPRIVATION THERAPY, THOSE THAT RESPONDED SHOWED DRAMATIC RECONDUCTION IN THE CONVERSION TO LACTATE, WHEREAS IN THE NON-RESPONDER THERE WAS NO CHANGE OR EVEN GOT HIGHER SO THERE'S SIGNIFICANT DIFFERENCE AFTER RESPONSE. IN COLLABORATION WITH SABRINA RONAN'S GROUP, IN A METASTATIC MODEL, BONE METASTASIS INJECTED IN THE LEG OF NEW MOUSE. WITHIN TWO DAYS AFTER TREATMENT, WAS A DRAMATIC REDUCTION IN LACTATE. SHE ALSO DID CELLS CORRELATION BETWEEN HYPERPOLARIZED MR HERE SHOWInlud THE BIG REDUCTION FOLLOWING TREATMENT OF ABOUT 45% SO WE ALSO SEE THE SAME RASH OWE LDH ACTIVITY, PROTEIN EXPRESSION AN mRNA EXPRESSION AND ANOTHER STUDY STUDENTS CORRELATED WELL BETWEEN THE LDH ACTIVITY ASSAYS AN WHAT HE SEE IN VIVO WITH HYPERPOLARRISM MRI. WE DEVELOPED THE COILS AND METHODS TO DO HUMANS BUT TESTED THE FIRST ON THE DOG.T SO WE SAW PROBABLY MORE LACTATE E WE SAW MORE LACTATE THAN WE TO IN THE HUMANS WHICH I'LL SHOW YOU IN A MINUTE BUT WE'RE ACQUIRING HERE, DATA WITH HIGH SNR WITH RESOLUTION OF .125 CCs IN TEN SECONDS. WE TESTED THESE METHODS ON CANCER PATIENTS USING YOURRRHEA INSERT HERE, IN THIS CASE WE GET ONE LITTLE PEAK BUT TELLING US THESE TECHNIQUES WORKED. WE DEVELOP THE POLARIZER IN THE CLEAN ROOM COLLABORATIVELY WITH GE THIS IS THE SET UP HERE INSTEAD OF HEATED DISILLUSION AND THIS PASS HERE, THE COOL' NEUTRALIZED THE FILTERS OUT STERILE EYEING BUOY FILTER, IT COMES UP COLOR AND HYPERPOLARIZED HERE IN THIS RECEIVE VESSEL AT PHYSIOLOGIC PH AND TEMPERATURE. THEY DID AN AWESOME JOB, QUITE ROUTINE BY THE END FOLLOWING ALL THE REGULATIONS. WE DESIGNED THE STUDY T PRIMARY GOAL WAS TO DETERMINE THE SAFETY OF FEASIBILITY OF HYPERPOLARIZED C-13 PIE RUE INVESTIGATE INVESTIGATE INJECTION PROVEN MEN WITH PROSTATE CANCER DOSE ESCALATION, SO THERE WAS IN EACH DOSE THREE GOT DYNAMIC, THREE SPATIAL IMAGING SO M EQUALS THREE STUDY DONE TEN TIMES. OVERALL PI BUT FROM INVESTIGATIONAL THERAPEUTICS GROUP. AND DOSE ESCALATION, THE RIGOROUS SAFETY TRIALS PRE-CLINICAL DATA AND PHARMACY PROCESS QUALIFICATION PERFORMED TO IND SUBMISSION DONE IN 2010. WE STUDIED 31 PATIENTS AND ALL DEMONSTRATED SAFETY AN FEASIBILITY WITH NO DOSE LIMITING TOXICITY. FUTURE CLINICAL STUDIES ARE REQUIRED TO INVESTIGATE CLINICAL VALUE. THESE ARE FROM OF THE SOME OF THE INITIAL STUDIES, REMINE YOU, WE ARE INJECTING PYRUVATE, LDH IS CONVERTING IT, IT'S NOW CHANGED THE FREQUENCY IS DIFFERENT. NUCLEUS IS ALIGNED WITH THE FEEL. IT DIES OUT ABOUT 80 TO 100 SECONDS BUT WE CAN SEE THE UPTAKE AT ITS CONVERSION AND REGIONS OF CANCER TO LACTATE. THE NORMAL VERY LITTLE, IT'S DIFFERENCE FROM THE CANINE PROSTATE, CELL DENSITY IS LOWER SO HIGHER IN CANCER AND LDH IS UP REGULATED IN THE CANCER. IN NORMAL REGIONS THERE'S REALLY NO DETECTABLE LACTATE GIVEN TECHNIQUES. WE GET MORE SENSITIVE WE'LL DETECT LOW LEVELS IN NORMAL TISSUE BUT IN CANCER VERY HIGH LEVELS OF LACTATE BIOPSY CONCERND PROSTATE. IN THIS CASE WE'RE DOING .7 CCs WE RECOLLECT GOT DOWN TO ABOUT .4, .35 IN SOME OF THE STUDIES. SARA NELSONs GROUP DEVELOPED SOFT WEAR AND OPEN SOURCE PACKAGE AS PART OF THE CENTER GRANT. HERE WE CAN SEE AREAS GREATER YOU CAN LOOK THROUGHOUT THE ENTIRE GLAND. EVEN AT THE DOSE -- IN SOME CASES WE CAN DETECT THE LACTATE SO THIS IS .28 MILIMILLILITERS PER KILOGRAM OF PYRUVATE BUT THE FINAL DOSE WAS .42-MILLILITERS SO ABOUT 35 MLs OR SO FOR AN AVERAGE MAN. THIS SHOWS IMAGES FROM THROUGHOUT THE WHOLE GLAND. IN THIS CASE BILATERAL CANCER DECKED BY BIOPSY ON IMAGING ONE SIDE, BUT IN THE HYPERPOLARIZED CARBON WE SEE LEVELS AS LEFT AS WELL AS RIGHT SIDE. WITH MR GUIDED BIOPSY, WE HAD ABILITY TO GO IN AND BIOPSY THAT1' REGION, IT WAS IN A SUBS WEB EXAM BUT ULTIMATELY BETTER THAN THE SAME EXAM. THIS REGION WAS BIOPSIED AND CONFIRMED TO BE CANCER. SO THIS, HERE IS MORE EXAMPLES IN DIFFERENT PATIENTS SHOWING ABILITY TO DO THIS. WE CAN ALSO LOOK AT THE DYNAMICS THROUGH A RAPID ACQUISITION OF SHOWING SIGNIFICANTLY DIFFERENCE DYNAMICS, THE RED CONSTANT BETWEEN PYRUVATE LACTATE SIGNATURE COMPLAINT HIGHER IN CANCER COMPARED TO VASCULAR VOLUME BY ORDER OF MAGNITUDE. SO IN SUMMARY, WE FOUND IT WAS SAFE, GOOD QUALITY DATA, AND THAT ARE SHOWED AND WE CAN SEE THAT THE MILLILITER PER KILOGRAM, PYRUVATE WAS SAFE AND APPEARED TO BE EFFECTIVE FOR THE GOALS OF THE STUDY BUT NEW STUDIES ARE REQUIRED. THIS IS THE NEW POLARIZER GE MAKING. IT IS A PLASTIC TUBING WITH A DIFFERENT COMPONENT IN IT. OUR PHARMACISTS DR. FARONI THAT OVERSAW THE TRIAL IS WORKING THE HEADACHE THIS A STERILE PACKAGE THAT CAN BE FILLED, AT THE PHARMACY AND SEN AROUND COUNTRY AND WORLD FOR HUMAN STUDIES, WE'RE WORKING ON TECHNIQUES TO DO VERY FAST IMAGE, SARA NELSON'S GRANT SUPPORTED BY THE NCI, HAS RIGHT NOW BEEN ABLE TO GET GOOD QUALITY DATA IN THE PRIMATE BRAIN, LOOKING FORWARD TO STARTING HUMAN GLIOMA STUDIES VERY SOON, BRAIN TUMOR STUDIES. WITH WE'RE WORKING WITH OUR ONCOLOGISTS TO DO NEW STUDIES WHICH THAT EAR DEVELOPING FOR NEW PREDICTIVE BIOMARKER FOR CANCER. THERAPY AND PROSTATE CANCER. THEIR REGULATORY MODIFYING THE IND, PAUL MENTIONED BEFORE, AND DRUG MASTER FILES FOR EACH DIFFERENT COMPONENT TO KEEP THEM THE SAME SO THE PORTION CAN BE MODIFIED AS THE TECHNOLOGY DEVELOPS, THIS ONE NEW CLINICAL STUDIES IN DIFFERENT PATIENT POPULATIONS, BRAIN TUMOR, RENAL CARP, LIVER METASTASIS, LIVER PRIMARY CANCER. MULTI-CENTER COLLABORATIONS, EXPECTED TO BE 10 TO 15 OF THESE POLARIZERS INSTALLED THE END OF NEXT YEAR. WE'RE WORKING ON STUDIES FOR INTERPATIENT VARIABILITY AND EFFECTIVE THERAPY. WE GOT NEW FUNDING TO LOOK AT PRE-SURGICAL L PATIENTS, CORRELATIONS WITH GRADE AN IT SHALL SHOE ANALYSIS. WE'RE ALSO WORKING ON (INAUDIBLE) WORKING ON A PROJECT TO DO CASTRATION RESISTANT PROSTATE CANCER WITH IMPACT (INAUDIBLE) AND P WE'RE -- NIBIB WE OTHER DEVELOPING THE TECHNOLOGY TO ALLOW US TO DO METASTATIC SITES. METASTATIC PROSTATE CANCER, RAPIDLY WITH HIGH RESOLUTION. I TALKEDDED PYRUVATE, THE FUTURE OF HYPERPOLARIZATION INCLUDES OTHER COMPOUNDS AN NEW PROBES OF METABOLISM AND I WANT TO ACKNOWLEDGE A WHOLE LARGE TEAM UCSF AND EXTERNAL COLLABORATORS AND OTHER SITES AND IN INDUSTRY AND ACKNOWLEDGE GRANT SUPPORT FROM THE NIH DISCOVERY AN GE FORK THE CLINICAL TRIAL AND GREAT ADVICE AND SUPPORT FROM THE NIBIB PROGRAM OFFICIALS HE WILL LYNNE MCLAUGHLIN WHO WORKED ON THE ROAD MAP INITIATIVE AND MORE RECENT CURRENT GRANTS DR. LIU HAS BEEN REALLY GREAT HELPING US. THESE ARE ALL THE PEOPLE THAT DID A LOT OF THIS WORK, JOHN (INAUDIBLE) AN SARA NELSON AS LEADING MUCH OF THIS WORK. THANK YOU FOR YOUR ATTENTION. [APPLAUSE] >> ALLUDED TO THE PATH OF DEVELOPMENT AND IT'S THEREFORE VERY APPROPRIATE AND WE'RE VERY PLEASED TO HAVE FROM OUR SISTER AGENCY THE FOOD AND DRUG ADMINISTRATION, DR. LEWIS JACQUES FROM CDR, -- DR. MASELLA, WELCOME. >> GOOD AFTERNOON, LADIES AND GENTLEMEN. IT'S A PLEASURE TO BE HERE TO DISCUSS REGULATORY PATH FOR GETTING ALL THESE EXCITING NEW MOLECULAR PROBES THAT CALL WORKING ON. AND READY FOR MARKETING. MY NAME IS LOU MARSELLA, CDER AND FDA AND I WOULD LIKE TO THANK THE ORGANIZERS FOR THE OPPORTUNITY TO BE HERE TO TALK TO YOU. THE FOCUS OF MY TALK IS PHASE 3 TRIALS DIAGNOSTIC THERAPEUTIC DRUGS, I'LL SHOW YOU EXAMPLES HOW IMAGING CAN BE USED IN CLINICAL TRIALS AND THEN WE WILL CONSIDER THE QUALITY AND QUANTITY OF THE EVIDENCE THAT IS NEEDED TO BE ABLE TO GET A DRUG APPROVED AND LEGALLY MARKETED IN THE UNITED STATES. BEFORE ANYBODY PANICS I'LL TAKE 15 MINUTES TO DO THIS. THE FOR THOSE INTERESTED, YOU WILL FIND A MORE DETAILED DATE CUSHION OF THIS TOPIC IN THIS GUIDANCE THAT IS IN DRAFT FORM AND THAT WE ARE HOPING TO FINALIZE THIS YEAR. IF YOU NEED ADDITIONAL INFORMATION, I HAVE GIVEN URLs FOR A COUPLE OF OTHER GUIDANCE, ONE, THE FIRST ONE WHICH IS SPECIFIC TO MEDICAL IMAGES PRODUCTS, WHICH ARE THOSE THAT YOU WORK WITH EVERY DAY. SECOND IS A GENERIC ONE THAT TALKS STANDARDS FOR EVIDENTIARY STANDARDS FOR EFFICACY FOR DRUG APPROVAL. SO LET'S BEGIN TO CONSIDER WHY -- WHAT WOULD BE THE USE OF IMAGING WITH WITH MOLECULAR PROBES YOU WORK WITH, OTHER AGENTS. SO ONE COMMON OBJECTIVE OF USING IMAGING IS TO PROVIDE FOR INSTANCE ADEQUATE ASSURANCE THAT STUDY SUBJECTS HAVE OR ARE SUSCEPTIBLE TO THE CONDITIONS THAT IS OF INTEREST IN THE CLINICAL TRIAL. AND ANOTHER USE COULD BE TO SHOW THEY MAYBE SUSCEPTIBLE, MORE SUSCEPTIBLE TO RESPOND TO THE INVESTIGATIONAL TREATMENT. SO IS A WAY OF ENRICHING THE TRIAL. IMAGING CAN ALSO PLAY A SUPPORTIVE ROLE IN THE ASSESSMENT OF SAFETY. I KNOW YOU'RE INTERESTED IN EFFICACY AND OF COURSE THE HOLY GRAIL WOULD BE THE ABILITY TO USE AN IMAGING OUTCOME AS PRIMARY EFFICACY END POINT IN A CLINICAL TRIAL FOR APPROVAL OF THE INVESTIGATIONAL DRUG AS DIAGNOSTIC AGENT OR THE SUPPORT -- TO SUPPORT APPROVAL OF THERAPEUTIC DRUG. SO THERE ARE NUMBER OF FACTORSES THAT DETERMINE WHETHER OR NOT AN IMAGING END POINT CAN BE USED AS EFFICACY OUTCOME. SO THE MECHANISM OF ACTION OF THERAPEUTIC DRUG THAT IS IMPORTANT, THE DRUG CLASS, THE NATURE OF THE DISEASE, CRITICALLY ALSO IS THE DATA THAT SUPPORTS THE RELATIONSHIP BETWEEN THE IMAGING OUTCOME AND THE CLINICAL OUTCOME. THERE'S ALSO PRECEDENCE FOR USE. FINALLY ALSO, CLINICAL TRIAL DESIGN ASPECTS THAT ALSO PLAY A ROLE IN THIS CONSIDERATION. IN THE CONTEXT OF IMAGING DRUGS, TYPICALLY THE PERFORMANCE OF THE DRUG WITH RESPECT TO TRUE STANDARD IN TERMS OF ASSESSING SENSITIVITY AND SPECIFICITY IS TYPICALLY WHAT WE USE. LET ME MENTION A BIT ABOUT THE STANDARDIZATION, USE OF IMAGING IN CLINICAL TRIALS REQUIRES SOME FORM OF STANDARDIZATION. I WAS PLEASED TO SEE DR. TAMAGNAN SHOW IMAGES FROM THE CO-FEE WHICH RESULTED IN A DRAMATIC CHANGE IN THE AOF THE IMAGES. BUT THAT IS SORT OF A EXTREME STANDARD. EXISTING MEDICAL STANDARDS FOR IMAGE ACQUISITION AND INTERPRETATION ARE APPROPRIATE FOR USE IN A NUMBER OF CLINICAL SITUATIONS. HERE, I'M REFERRING TO THE USE OF A IMAGING AGENT FOR THE APPROVAL OF A THERAPEUTIC DRUG. SO MAYBE APPROPRIATE TO USE SITE AVAILABLE STANDARDS, PARTICULARLY IN CASES WHERE YOU HAVE FOR INSTANCE A RANDOMIZED DOUBLE BLIND CLINICAL TRIALS WHERE IMAGING MODALITIES WIDELY AVAILABLE, IT WILL INTERPRETATION IS STANDARD AND THERE'S NO DOUBT ABOUT THE POTENTIAL FOR BIAS. IN OTHER CASES, STANDARDIZATION CAN BECOME MORE CRITICAL. WE'RE CONTROL OF BIAS OR VERIFY CASE OF IMAGING DATA BECOMES IMPORTANT THIRD PARTIES CENTRALIZED I WILL IMAGINE INTERPRETATION IS SOMETHING THAT WE TYPICALLY RECOMMEND. LET ME SHIFT GEARS AND TALK ABOUT THE EVIDENTIARY STANDARDS FOR DRUG APPROVAL AND FOR IMAGING AGENTS THE STANDARDS DO NOT DIFFER OPPOSED TO ANY OTHER TYPE OF DRUG. SO HISTORICALLY IN 1962, CONGRESS AMENDED THE FEDERAL FOOD DRUG AND COSMETIC ACT TO ADD THE REQUIREMENT THAT TO OBTAIN MARKETING APPROVAL, DRUG MANUFACTURE NEEDED TO DEMON INVESTIGATE THE EFFECTIVENESS OF THEIR PRODUCTS. THROUGH THE CONDUCT OF WELL CONTROLLED ADEQUATE CLINICAL STUDIES. BEFORE THE PASSAGE OF THE ACT IN 1938, IN 1962 AMENDMENTS MANUFACTURERS ONLY NEEDED TO SHOW THAT DRUGS WERE SAFE. BEFORE THAT OF COURSE ANY DRUG COULD BE MARKETED. THERE WERE NO LEGAL REQUIREMENTS. SO THE NEW LAW IN 1962 ESTABLISHED A REQUIREMENT THAT DRUG PRODUCTS ESTABLISH EFFECTIVENESS BASED ON SUBSTANTIAL EVIDENCE. TYPICALLY MANY THE DRUG APPROVAL PROCESS WHAT HAPPENS IS THAT CONGRESS PASSES LAW AND THEN FEDERAL AGENCIES DEVELOP REGULATIONS WHICH HAVE THE FORCE OF LAW THAT EXPAND ON WHAT CONGRESS INTENDED. THEN WE HAVE GUIDANCE THAT DON'T HAVE A LEGAL REQUIREMENT BUT VERY USEFUL TO CONSIDER. SO WHAT IS MEANT BY SUBSTANTIAL EVIDENCE FOR MARKETING APPROVAL? CLINICAL TRIALS NEED TO BE ADEQUATE AND WELL CONTROLLED. WHAT THIS MEANS IS TRIALS SHOULD BE DESIGNED TO DISTINGUISH THE EFFECT OF THE DRUG OTHER INFLUENCES, CHANGE IN PLACEBO EFFECT AND BIASED OBSERVATION. THE TRIALS REQUIRE A VALUE LID COMPARISON WITH A CONTROL TO PROVIDE SOME FORM OF QUANTITATIVE ASSESSMENT OF THE DRUG EFFECT. DETERMINATION OF THE QUANTITY OF THE EVIDENCE IS MORE SUBJECTIVE. THE GUIDANCE EARLIER MENTIONS EXAMPLES WHERE ON BASIS OF ONE STRONG ROBUST RESULT FROM A SINGLE TRIAL, A DRUG CAN BE APPROVED. AND FINALLY ALSO IT'S IMPORTANT TO MENTION FOR DRUG APPROVAL, THERE IS A RISK BENEFIT CONSIDERATION THAT PLAYS A ROLE. THERE NEEDS TO BE A FAVORABLE BALANCE IN TERMS OF WHATEVER RISKS THERE, NEED TO BE BALANCED BY BENEFITS. THIS IS TYPICALLY NOT AN ISSUE WITH IMAGING DRUGS IF ALLUSIVETY CONCERN WITH IMAGING DRUGS IS WE WANT TO MAKE SURE THEY DON'T PROVIDE INCORRECT INFORMATION THAT COULD RESULT IN PATIENT HARM. WE DON'T HAVE THE TOXICITY CONCERNS FOR THERAPEUTIC DRUGS. THE TWO CRITICAL FACTORS THAT ARE IMPORTANT FOR APPROVAL OR DRUGS IS THE PERFORMANCE, THE METHODS USED TO ESTABLISH EFFECTIVENESS OF THE DRUG. THESE ARE AS DIAGNOSTIC AND THERAPEUTIC, THEY RELIABLE. SO AGAIN, IN THE CONTEXT OF IMAGING DRUGS, THE TYPICAL COMPARETOR IS A TRUE STANDARD. IN ADDITION TO HAVING A RELIABLE ASSESSMENT OF THE PERFORMANCE OF THE TEST, IT'S ALSO IMPORTANT TO ESTABLISH THAT THE TEST ALSO IS CLINICAL VALUE. IN THE CASE OF IMAGING, AS DAUNTING AS THE REQUIREMENTS MAY SEEM STANDARDS ARE ACTUALLY NOT AS RIGID AS THEY ARE FOR THERAPEUTIC DRUGS TO SO IN THE CONTEXT OF IMAGING PRODUCTS WE WILL ACCEPT SELF-EVIDENT SOME DEMONSTRATION OF IMAGING BASED OUTCOME. FOR THIS WE RELY HEAVILY ON HISTORICAL PRECEDENT SO NOBODY WILL QUESTION THE VALUE OF RADIO LOGIC VERBALIZATION OF A FRACTURE OR TUMOR. HOWEVER VISUALIZATION OF A TARGET RECEPTOR IN THE BRAIN BY A NOVEL MOLL QUEUE MAY NOT BE SELF-EVIDENT SO THE DATA THAT WOULD BE REQUIRED FOR THAT WOULD BE DIFFERENT. BUT IN THOSE CASE IT IS RELIANCE TYPICALLY IS BASED ON AN APPROVED PRODUCT THAT WORKS IN A SIMILAR FASHION OR STANDARD. WE TYPICALLY DO NOT REQUIRE CLINICAL OUTCOMES. WE DON'T REQUIRE CLINICAL OUTCOMES ARE MORE DIFFICULT TO COME BY BECAUSE THEY WOULD REQUIRE IN TERM OF PATIENT LIVES OR FEELS BETTER. THE TYPICAL ADVICE WE GIVE TO DRUG MANUFACTURER OR INTERESTED IN DEVELOPING PRODUCT T FOR CLINICAL USE, IS TO REALLY MORE ON STRUCTURAL END POINTS, PHYSIOLOGICAL END POINT, CHEMICAL END POINTS. THE NEXT TIER IF YOU WILL IN TERMS OF DIFFICULTY IS DIAGNOSTIC END POINT WHICH REQUIRES MORE RIGOROUS ASSESSMENT. FINALLY, THE HIGHEST THEY SHALL HOLD WOULD BE A THRESHOLD WHICH REQUIRES CLINICAL YOU COMES. OBJECTIVE TE UPON STATION THAT THE DRUG IS IN FACT MODIFYING CLINICAL OUTCOMES IN TERMS OF NOT A PHYSICIAN, A TESTING THAT THIS IS USEFUL BUT ACTUALLY HAVING AN OUTCOME DESIGNING THE TRIAL SUCH THAT THE IMAGING AGENT IS USED TO MANAGE -- TO MAKE THERAPEUTIC DECISIONS AND THEN THE FINAL OUTCOME OF THE DECISIONS WOULD BE MEASURED. SO THE -- IN DEVELOPING THEN AND TAKING ONE OF YOUR -- THESE PROMISING AGENTS TO THE MARKET, WHAT NEEDS TO BE DONE FOR DEVELOPMENT IS CONSIDER IN THE EFFICACY STAGE HOW MEANINGFUL THE CLINICAL END POINT IS. THE NEXT CRITICAL THING IS TO DETERMINE WHAT APPLICABLE IMAGING STANDARDS NEED TO BE. IN SOME CASES THEY NEED TO BE RIGOROUS AND SOME OTHERS MAYBE NOT. THE FDA HAS A -- FDA IS LIKE -- WE ALL NEED FOLKS. BEFORE THEY SUBMIT AN IND EFFICACIOUS OF DRUG DEVELOPMENT. SO I MET A NUMBER OF YOU AND A NUMBER OF YOU I HAVEN MET I REVIEWED YOUR CLINICAL TRIALS. WE ENCOURAGE YOU TO HAVE INTERACTIONS WITH US TO DISCUSS YOUR PLANS FOR TAKING -- FOR DOING PRE-CLINICAL STUDIES FOR DESIGNING TRIALS. IF WE'RE NOT THE RIGHT DIVISION WE CAN DIRECT YOU TO WHICH DIVISION WITHIN THE FDA YOU NEED TO TALK TO. WHEN YOU CHOOSE A PRIMARY END POINT DETERMINE YOUR DRUG IS EFFECTIVE, YOUR DIAGNOSTIC AGENT REALLY WORKS, THERE'S A CONTINUUM OF END POINTS, SOME END POINTS PROVIDES SELF-EVIDENT, THERE'S T ANOTHER CATEGORY OF ENPOINTS, SURROGATE END POINTS WHICH ARE MEET A DIFFERENT STAN DART. THEY ARE LIKELY TO PREDICT BENEFIT SO FOR THESE PRODUCTS IF THEY ARE DESIGNED ADDRESS AN UNMET MEDICAL NEED, A SERIOUS CONDITION FOR DIAGNOSTIC ORTHER PEWICLY WHICH THERE'S NO ACCEPTABLE ALTERNATIVE, THEN THERE IS A REGULAR HATORY PATHWAY FOR GETTING THE PRODUCT ON THE MARKET BASED ON A SURROGATE END POINT. BUT THAT'S SORT OF -- WOULD STILL REQUIRE DATA BE ACQUIRED POST MARKETING TO ACCOMPLISH CLINICAL EFFICACY. THEN SORT OF THE LOWEST THRESHOLD, THE FLOOR LEVEL, WOULD BE BIOMARKERS WHICH ARE USED FOR PHASE # AND PHASE 2 END POINTS TO MAKE GO OR NO TWO DECISIONS IN TERMS OF HOW TO DEVELOP A DRUG. EVEN FOR THIS ONE, BOTH THE EMA AND THE FDA NOW HAVE WHAT THEY CALL BIOMARKER QUALIFICATION PROCESSES. THE ADVANTAGE OF THESE PROCESSES IS THE FDA WILL REVIEW DATA AVAILABLE PUT A STAMP OF APPROVAL BIOMARKER FOR SPECIFIC CONTEXT OF USE. SO THIS SORT OF HAS TWO ADVANTAGES, THINKING PAROCHIALLY AN ADVANTAGE FOR FDA BECAUSE WE DON'T HAVE TO REVIEW THE DATA ALL THE TIME WE REVIEW IT, WE MY IT WAS A RELIABLE IMAGING BIOMARKER, AND THIS SPECIFIC CONTEXT AND THE ADVANTAGE TO ACADEMICIANS SUCH AS YOURSELVES OR INDUSTRY TO SAY OKAY THERE IS A REGULATORY PATHWAY, FDA HAS AGREET GREED FOR THIS CONTEXT OF USE THIS IMAGING OUTCOME IS USEFUL. THIS IS MY LAST SLIDE I WANT TO CONCLUDE WITH KEY POINTS, WHAT DOES IT TAKE TO GET A PRODUCT LEGALLY MARKETED, RECEIVE FDA APPROVAL TO BE LEGALLY MARKET IN THE U.S.. THERE HAS TO BE SUBSTANTIAL EVIDENCE OF EFFICACY. ONE WAY I CAN PUT IT GIVEN THIS ODD YEN, IT HAS TO BE GOOD SCIENCE. AND I CAME FROM AN ACADEMIC RESEARCH ENVIRONMENT ONCE, AND THE AMAZING THING IS REGULATORY SCIENCE IS A SCIENCE THAT REQUIRES A LOT -- IT'S NOT INTUITIVE. THERE'S A LOT OF LEGAL PRECEDENT, SO I HEARD QUESTIONS THIS MORNING ABOUT HOW DO WE LEVERAGE THE RESEARCH THAT WE DO, HOW DO WE MOVE PRODUCTS. IT'S NOT SIMPLE, BUT IT IS TRANSPARENT, THERE ARE STANDARDS, AND -- BUT THERE NEEDS TO BE AN INFRASTRUCTURE, THERE NEEDS TO BE COLLABORATION. I HAVE SEEP IN THE PAST, FOR INSTANCE UNIVERSITY DEVELOPED CONSORTIA ORLATORY AFFAIRS GROUPS THAT SPONSOR INDs ON BEHALF OF INVESTIGATORS. IT IS COMPLEX, INTENSIVE, NOT ADS INTUITIVE. SO WE AT FDA ARE FROM TO HELP. WE CAN MEET WITH YOU, WE CAN GIVE YOU ADVICE, IT IS IMPORTANT TO -- FOR YOU TO PARTNER WITH INDUSTRY IF POSSIBLE OBVIOUSLY THAT WOULD BE THE IDEAL BUT THERE ARE VARIOUS CONTRACTS ORGANIZES THAT PROVIDE HELP AND ADVICE. ICE NOT EASY, SO THE OBJECTIVE IS STANDARDS ARE REALLY THE EVIDENTIARY STANDARDS ARE CONSISTENT BASICALLY ACROSS ALL DRUGS, IN THE CASE OF MEDICAL IMAGING AGENTS, THERE ARE REQUIREMENTS WHICH MAY NOT BE AS BURDENSOME BECAUSE THEY DON'T REQUIRE CLINICAL OUTCOMES FOR DEMONSTRATION OF EFFECTIVENESS. YOU CAN LOSE STRUCTURAL END POINTS OR PHYSIOLOGIC END POINTS IN SPECIFIC CONTEXT. THE OTHER THING IMPORTANT THE ESTABLISH IS IMAGING METHODS NEED TO BE WELL DEFINED AND VALUABLE. PARTICULARLY FOR MOLECULAR PROBES IS CRITICAL. IN CHOOSE AFFECT IMAGING END POINT, THE FINAL POINT TO UNDERSCORE IS TO CONSIDER HOW MEANINGFUL THE END POINT IS. AND AGAIN, IT GOES ANYWHERE FROM BIOACTIVITY WHICH IS USEFUL FOR EARLY PRODUCT DEVELOPMENT TO END POINTS THAT ARE MORE CONSISTENT WITH ESTABLISHED BENEFITS. THOSE ARE MY COMMENTS THAT I LOOK FORWARD TO QUESTIONS IF THERE ARE ANY AT THE DISCUSSION PERIOD. THANK YOU. >> EARLIER TODAY WE HEARD THE PHRASE GOING TO REIMBURSE AND WE'RE GRATIFYD TO HAVE THE REPRESENTATIVE FROM OUR SISTER 'GENERAL CITY CMS, DR. -- LET ME WELCOME DR. LOUIS JACQUES WHO WILL BE ADDRESSING MEDICARE COVERAGE OF MOLECULAR IMAGING. DR. JACQUES. >> SEE IF I CAN GET TO MY SLIDES HERE. IN THE END IT'S ALWAYS WHO IS GOING TO PAY FOR THIS STUFF WHICH I THINK EXPLAINS MY THOUGHT ON THE AGENDA. I WAS HERE EARLIER TO MORNING, I SHOWED UP AROUND 10:15 SO I DID HEAR THE PEOPLE MENTIONING THE THE PLACE HAVING TO WORK AT THIS POINT. AND ONE THING THAT WAS MOST INTERESTING TO ME BEFORE I GET TO MY SLIDES, THERE WAS TALK BEFORE LUNCHTIME ABOUT STANDARDIZATION, I WANT TO SPEND A MINUTE ON A LITTLE ANECDOTE. ABOUT SECH YEARS AGO COLLEAGUES IN THE NCI IMAGING SHOP INVITED ME TO A SYMPOSIUM AT COLLEGE PARK ON OPTICAL IMAGING FOR KAREN.8, THERE'S TALK ABOUT BARE RAT'S ESOPHAGUS, IF YOU STICK A SCOPE DOWN AND SHINE LIGHT AND LOOKS THIS COLOR, WHAT DOES THAT MEAN? AND IN THE AUDIENCE WERE NOT ONLY FOLKS FROM THIS AGENCY BUT PEOPLE FROMNIST, THERE WAS ALSO AT LEAST ONE VENTURE CAPITALIST IN THE AUDIENCE. I REMEMBER GETTING UP AND TELLING THEM, IT SEEMS FROM YOUR CONVERSATION YOU GUYS CAN'T AGREE ON WHAT WHITE LIGHT IS. IF YOU CAN NOT STANDARDIZE WHAT WHITE LIGHT IS HOW DO ANY OF US HAVE ANY INTEREST IN WHATEVER YOU SAY IS RED, PINK, PURPLE OR ANYTHING ELSE. I'M TOLD WITHIN A YEAR THEY ACTUALLY ADOPTD STANDARDS FOR VARIOUS COLORS OF LIGHT AND I WAS TOLD THAT THAT PUSH ACTUALLY CAME FROM THE VENTURE CAPITAL FOLKS BECAUSE THEY SAID YOU'RE NOT GETTING ANY MORE MONEY IF THE PAYERS ARE ALREADY SAYING THAT YOU'RE THIS FAR OFF BASE. SO WITH THAT, AS I GUESS A BIT OF INTRO, LET ME GET STARTED. LET'S TRY IT THIS WAY. LET'S HAVE GIVENS FOR TODAY. FIRST IS A DOINGNOSTIC TEST PER SE RARELY THERAPEUTIC UNYOU ADMINISTER VITAMIN B 12, THAT'S A FIELD TEST PLATFORM AT THIS POINT YOU'RE PROBABLY NOT GOING TO IMPACT THE PATIENT OUTCOMES. FROM OUR VIEW DIAGNOSTIC TESTING PER SE WILL ACHIEVE BENEFITS THROUGH CHANGES IN PHYSICIAN MANAGEMENT OF THE PATIENT. AND WE REALIZE THAT THAT MAY COME AT A TRADE OFF OF SOME SHORT OR LONG TERM ADVERSE EVENTS DEPENDING THE PARTICULAR AGENTS THAT HAVE INVOLVED. WE DO THINK IT'S IMPORTANT TO CONSIDER THE CLINICAL SCENARIO IF YOU HAVE A CONDITION THE PATIENT IS IN FRONT OF YOU AND SOMETHING HAS TO BE DONE RIGHT NOW. IT'S A DIFFERENT PARADIGM THAN IF YOU HAVE A PATIENT ASYMPTOMAT UK AN FISHING FOR DIAGNOSIS, -- ASYMPTOMATIC AND TELLING HIM HE'S SICK OR HAS A PRE-CONDITION. THEE WHICH IT'S IMPORTANT TO RECOGNIZE THAT AN IMPROVEDDED HEALTH OUTCOME ALSO INCLUDE REDUCED EXPOSURE TO MEDICAL MISADVENTURE. SO IF YOU CAN AVOID A TOXIC DRUG BECAUSE OF DIAGNOSTIC TEST RESULT WE THINK THAT'S IMPORTANT, EVEN IF THAT'S NOT CURE -- EVEN IF THAT'S NOT LONGER REDUCED MORTALITY. CONCEPTUALIZATION OF WHAT IT'S USED FOR, THESE ARE THE FOURTH PLACES OR PERIMETERS, WHERE PEOPLE GENERALLY ASK US PARTICULAR QUESTIONS ABOUT THIS, THAN FINALLY PLAIN OLD CLINICAL DIAGNOSTIC TESTING. MOST OF YOU WILL RECOGNIZE THIS, IT'S FROM THORN BERRY AND FRY BECK DEPENDING WHO YOU GIVE PRIVACY TO. WE DIDN'T INVENT THIS, THIS IS HAS BEEN AROUND A LONG PERIOD OF TIME, THOUGH AROUND DIAGNOSTIC IMAGING IT'S APPLIED MORE BROADLY AROUND DIAGNOSTIC TESTING IN GENERAL. THIS IS WHAT WE REALLY WANT. SO THE OTHER LOU WII BEFORE WE TALKED ABOUT WHAT YOU NEED TO DO FOR FDA, WHAT YOU NEED FOR CMS. WE REALLY WANT CLINICAL UTILITY. I WILL GET A COUPLE OF SLIDES LATER, WE DON'T NECESSARILY HAVE TO GET THERE DIRECTLY. BUT THAT IS WHAT WE IDEALLY WANT. IF YOU WANT US TO BE ENTHUSIASTIC ABOUT YOU AS OPPOSED TO OKAY, FINE, I GUESS WE HAVE TO LET THEM IN. COME WITH CLINICAL UTILITY, WE GET SOMETHING BETWEEN TECHNICAL EFFICACY AND DIAGNOSTIC ACCURACY. OFTEN THIS IS GRAY MARKET LITERATURE AND THE ONLY PERSON IS THIS HAPPENS TO BE THE MANUFACTURERS OR OTHERS WHO HAVE A FINANCIAL INTEREST IN THE TECHNOLOGY, WHERE WE END UP, WHAT WE COPE WITH IS THIS THREE TO FOUR DIAGNOSTIC IMPRESSION OR DIAGNOSTIC ACTION. WHAT IMPACT DOES THE TEST RESULT HAVE ON RECOMMENDATION MADE BY PHYSICIANS. THE PERSUASIVENESS OF ARGUMENTS BASED ON THAT CONSTRUCT ARE DEPENDENT WHAT IS OTHERWISE NEAR KNOWN AS THE DISEASE ITSELF. I.E. THE CLINICAL MILIEU WHICH THAT TAKES PLACE. SO BRIEFLY FOR THOSE WHO AREN'T ALREADY PAINFULLY FAMILIAR WITH MEDICARE. WE ARE A NATIONAL PROGRAM WITH LOCAL ADMINISTRATORS. ADMINISTRATIVE CONTRACTOR, THE ANTHEMS THE PAULMETTOS, WISCONSIN PHYSICIAN SERVICES, AS NOTE OF SYMPATHY WHEN I WAS HIRED IN 2003, BEFORE THAT I WAS THE CURRICULUM DEAN AT GEORGE TOWN MEDICAL SCHOOL AND WAS HAVING A GREAT TIME THERE BUT I DECIDED IT WAS TIME TO WORK HAIL BIT CLOSER TO WHERE I LIVED. AND THEY ASKED ME IN MY INTERVIEW WHY DO YOU WANT TO WORK FOR MEDICARE? ANSWER WAS YOU GUYS HAVE BEEN A THORN IN MY SIDE FOR 20 YEARS, DRG CAME OUT LAST YEAR OF RESIDENCY, I HAVE BEEN UNABLE TO BEAT YOU. I MIGHT AS WELL JOIN YOU. SO COVERAGE DECISIONS CAN BE MADE LOCALLY OR NATIONALLY. WE CAN DO THEM FOR HALLLY AND ALSO INFORMALISM THESE ARE THE REGIONAL JURISDICTIONS AND THESE CONTRACTS ARE COMPETED FROM TIME TO TIME SO THERE ARE ONE OR TWO JURISDICTIONS IN TRANSITION. , SO HERE IS PET COVERAGE CURRENTLY. NATIONALLY ALL USES ARE NON-COVERED UNLESS WE HAVE COVERED THEM, THIS IS A LONG STANDING POLICY THAT DATES FROM 1990s WORK COVER FDG PET FOR ON COLOGIC USES UNDER RUBRIC OF CURRENT EVIDENCE DEVELOPMENT, THAT INITIATIVE WAS LED BY BAUERRY SIEGEL AND BRUCE HILLMAN AND OTHERS AND THE LATE DEB COLEMAN, BECAUSE THE CONSTRUCT IS FAIRLY REGIMEN DRIVEN, CANCER CARE WE WERE ABLE TO WITH FDG TO ACCEPT EVIDENCE OF INTENDED CHANGES THIS MANAGEMENT BY CREATING PHYSICIANS TO GET THAT FROM CLINICAL UTILITY OUTCOME REALIZING CANCER CARE IS NOT Z GOOD A WE WOULD LIKE I TO BE, NONETHELESS IF YOU CAN AVOID FUTILE EXPOSURE TO SOMETHING THAT WILL GIVE YOU A HORRIFIC NEUROPATHY, WE THINK IT BETTER THE AVOID NEUROPATHY IF THE DRUG IS NOT HELPFUL. WE HAVE CONDITIONAL COVERAGE FOR BONE MEDS AND WE HAVE COVERAGE FOR RUED CARDIAC USE. WE DID MAKE A CHANGE EARLIER THIS YEAR, FOR SOME INDICATIONS PET ISN'T A NEW TECHNOLOGY, IT'S BEEN AROUND SINCE 1970s, AT LEAST IN MY CURSORY LOOKS FOR THE HISTORY OF WHEN PET HIT THE NATIONAL MEDIA. WE SAID REFLECTING CANCER CARE IS RELATIVELY PROTOCOL DRIVEN, NEW PROPRIETARY FDA APPROVED AGENTS ARE COVERED BY LOCAL CONTRACTORS, YOU DON'T HAVE TO COME TO US FOR PROVISION, THE NON-COVERAGE WAS REMOVED THIS YEAR FOR LABELED USES IN ONCOLOGY. IF YOU WANT IT FOR UNLABELED I DID CASES THEN YOU NEED TO COME US BUT IF YOU STICK THE LABEL YOU CAN TALK CLINICAL CONTRACTORS -- CONTRACTORS. THIS IS TO REACH THE NECESSARY STANDARD FOR DIAGNOSE OF TREATMENT OF ILLNESS OR INJURY, THERE ARE A DOZEN OTHER WAYS SOMETHING CAN REASONABLE AND NECESSARY BUT THEY DEAL WITH THINGS LIKE PNEUMOCOCAL VACCINE, HOSPICE CARE AND THINGS ALONG THOSE LINES. WE ALSO HAVE RULE MAKING AN DIAGNOSTIC TESTS. THE TEST NEEDS TO BE USED ORDERED BY THE PATIENTS TREATING PHYSICIAN. THIS SNOT EVERYBODY SHOW UP AND THERE'S A TEST, THAT DOCTOR HAS TO USE THE TEST IN THE MANAGEMENT OF BENEFICIARY PROBLEM SO LOOKING AT EVIDENCE WE ARE LOOKING AT HOW WOULD A RATIONAL PHYSICIAN GIVENTHER PUTTIC OPTIONS THAT ARE AVAILABLE, WHICH MAY EVEN INCLUDE WATCHFUL WAITING, HOW WOULD A REASONABLE PHYSICIAN ACTUALLY INCORPORATE THIS TEST INTO THE MANAGEMENT OF THE PATIENT? THE IMPORTANT WORDS ARE IN RED. PROVIDE ADEQUATE EVIDENCE, EVIDENCE HIERARCHIES ARE NOT NEW, WE DIDN'T INVENT THEM AS WE GET LOWER EVIDENCE HIERARCHY YOU EXPOSE YOURSELF TO INCREASE RISK OF BIAS AN CONFOUNDING. OUR AGENCY IN CONTRAST TO FDA RELIES ON PUBLISHED PEER REVIEWED EVIDENCE. OPPOSED TO THE TREMENDOUS INFRASTRUCTURE FDA HAS INTERNALLY TO REVIEW RAW DATA. WE'RE WILLING TO LOOK AT RAW DATA BUT BECAUSE OUR REQUIREMENTS ARE AROUND TRANSPARENCY, I.E., IF WE MAKE A DECISION, THERE IS STATUTORY EXPECTATION THE PUBLIC COULD LOOKED THE SAME EVIDENCE WE LOOKED AT ESSENTIALLY TO AGREE WITH OR DISAGREE WITH US. THAT MOVES US MORE TOWARD THE PARADIGM WHEREVER WE GET WE'LL IN GENERAL BE SEEABLE BY MEMBERS OF THE PUBLIC. THE INCREMENTAL INFORMATION OBTAINED BY THE NEW DIAGNOSTIC TECHNOLOGY COMPARED TO ALTERNATIVES, NOT HEAD TO HEAD COMPARATIVE EFFECTIVENESS, THIS MEANS IN THE CURRENT CLINICAL SCENARIO, PHYSICIANS ARE GETTING THIS INFORMATION SOMEHOW OR THEY ARE DEALING WITH THE ABSENCE OF THIS INFORMATION. SO IF WE ADD YOUR DIAGNOSTIC INFORMATION HOW DOES THAT CHANGE PHYSICIANS THAT IMPROVE CLINICALLY MEANINGFUL OUTCOMES IN MEDICARE BENEFIT FIB AREAS. ANOTHER CHALLENGE IS PEOPLE WHO ARE MEDICAL BENEFICIARIES A TYPICAL BENEFICIARY IS 74, 75 YEARS MR. ELLIS: WITH MULTIPLE COMORBIDITIES TAKING HALF A DOZEN MEDICATIONS, EXACTLY PEOPLE WHO DON'T GET ENROLLED INth CS. SO IF WE'RE FACED OR CONFRONTED WITH EVIDENCE BASED ON LARGELY YOUNGER HEALTHIER POPULATION, AND IF THERE IS REASON TO BELIEVE BASED ON SOUND CLINICAL LOGIC, EITHER MANIFESTATION OR PROGRESS OF THE DISEASE ITSELF OR RESPONSE OR TOLERABILITY OF TREATMENT WILL BE AFFECTD BY THE CHANGES THAT WE KNOW ACCOMPANY AGE AND/OR CHRONIC DISABILITY, THAT CREATE AS SIGNIFICANT HURDLE FOR US IN TERMS OF GENERALIZING THOSE BITS OF EVIDENCE TO OUR POPULATION. GRAPHICALLY ON THE LEFT YOU HAVE WHAT USUALLY HAPPENS TO THE PATIENT IN THE CURRENT FA STATUS QUO. RIGHT SIDE YOU HAVE A NEW TEST, IF IT LEADS TO THE SAME THERAPY ONE ASKS WHAT'S THE POINT OTHER THAN INCREASING THE BURDEN TO THE PATIENT IN THE SYSTEM AND ADDING THE POSSIBILITY THAT A MEDICAL ERROR MIGHT BE MADE IF THE INFORMATION GETS SCREWED UP IF YOU GET TO A DIFFERENT THERAPY WITH BETTER OUTCOME WE'RE ENTHUSIASTIC, WE WILL BEND OVER BACKWARDS TO TRY TO FIND A WAY TOO COVER YOU. ON THE OTHER HAND IF A DIFFERENCE THERAPY GETS TO A WORST OUTCOME WE ASK YOU WHY YOU WOULD WANT TO KEEP COOING IT. IF YOU GET THE SAME OUTCOME YOU GOT THERE BEFORE BUT MORE EFFICIENTLY, THAT WAS A PLACE TO HAVE A CONVERSATION. THESE ARE SOME OF THE QUESTIONS WE MIGHT ASK. WHAT ARE ARE THE ACTUAL DATA? ARE THESE COLOR, NUMBERS, SOMEBODY LOOKING AT SLIDES. WHAT ARE THE CLINICAL INFORMATION THAT THE DATA PROVIDE, HAVE GOTTEN THIS BEFORE? WHAT'S DIFFERENT BECAUSE OF THIS, AND WHAT ARE THE ADVANTAGES AND DISADVANTAGES OF BASING DECISIONS ON THIS NEW TEST. HERE IS A FEW NOT NECESSARILY RELATED TO THE CLINICAL OUTCOME OF THE PRIMARY DISEASE. IS IT LESS INVASIVE? INSTEAD OF HAVING AND ACHIEVE THE SAME CONFIDENCE AND DECISION MAKING. IS THERE CLINICALLY SIGNIFICANT FASTER TURN AROUND, AND THE PATIENT WIDDLES THEIR THUMBS IN THAT PERIOD OF TIME, IS THERE A MEANINGFULLY QUICKER TURN AROUND THAT'S AN ADVANTAGE. CAN YOU REDUCE PATIENT EXPOSURE TO THINGS THAT TEND TO CAUSE ADVERSE EVENTS. IS THERE A CLINICALLY SIGNIFICANT BROADER AVAILABILITY OF CURRENT PARADIGM RESTRICTED TO MAYBE ONE OR TWO SPECIALIZED CENTERS IN THE UNITED STATES AND YOU CAN GET AS CONFIDENT A RESULT WITH SOME OTHER TEST PARADIGM. WE'RE INTERESTED IN THAT. HOW THAT COMES OF INTEREST. I'M USUALLY TALKING TO THE CANCER COMMUNITY, IF YOU HAVE A PATIENT BED BOUND THE PROBLEM IS THE PATIENT IS BED BOUNTY. WHEN YOU'RE BED BOUND YOU CAN'T GO TO THE BATHROOM BY YOURSELF, YOU CAN'T FEED YOURSELF, A HAIR'S BREATH AWAY FROM YET ANOTHER ULCER, YOU ARE SOCIALLY ISOLATED. THE FACT THE PATIENTER PATIENT SCAN LOOKS BETTER OR SCORE INDEX GOT BETTER, NOT PERSUASIVE IF THAT PATIENT IS STILL IN BED AND IN PAIN. WE ARE INTERESTED IN FUNCTIONAL OUTCOMES. WE CALL THINGS DISEASE BECAUSE THEY DISOUR EASE. HOW DO YOU RESOLVE THOSE THING? THERE ARE MANY ABNORMALITIES IN THE HUMAN BEEN BUT BECAUSE THEY DON'T BOTHER US THEY DON'T IMPACT HOW WE CONDUCT OUR LYES WE MIGHT NOT LABEL THEM DISEASE. HOW DO YOU ACTUALLY MAKE THE PATIENT FEEL BETTER? THIS IS OUR PROCESS, WE HAVE ALMOST ZERO FLEXIBILITY AROUND THIS PROCESS. BUT WE DO INCORPORATE PUBLIC TENT, ONE IS REQUIRED BY LAW ON PROPOSED DECISION, THE OTHER ONE WE SIMPLY JUST DO BECAUSE WE'RE NICE PEOPLE, WHEN WE FIRST OPEN IT. IF ANYBODY WANTS MORE DETAIL (INDISCERNIBLE) AN ATTORNEY MY DEPUTY SHE AND I CO-AUTHORED SOMETHING FOR THE REGENERATIVE MEDICINE COMMUNITY, AT THEIR INVITATION. THEY HISTORICALLY HAVE NOT ENGAGED WITH MEDICARE, AND RATHER THAN REPEAT MISTAKES OF OTHER INDUSTRIES TO TALK TO US BEFOREHAND. WITH THAT SAID THIS IS OUR COVERAGE WEBSITE, ANYTHING I SAID CAN BE wEFERENCED THERE AND I HAVE THE TYPICAL US GOVERNMENT EMAIL. [APPLAUSE] (OFF MIC) (OFF MIC) (INAUDIBLE) >> YES. THERE ARE STATUTORY PROHIBITIONS AGAINST ROUTINE COVERAGE OF SCREENING EXCEPT CONGRESS ITSELF CREATE PARTICULAR EXCEPTIONS. CONGRESS CREATED BY STATUTE, COLORECTAL SCREENING PAP TESTS THINGS ALONG THOSE LINES. OTHER PREINVENTORY ACTIVE SERVICES INCLUDE PNEUMOCOCAL VACCINE THINGS LIKE THAT BUT NARROW. WE HAD LEGISLATION IN 2008 MEDICARE IMPROVEMENTS FURPHY SESSION, PROVIDERS THAT GAVE US THE AUTHORITY TO FOR CONSIDER THE POSSIBILITY OF MEDICARE COVERAGE IF THREE CONDITIONS ARE MET. NUMBER ONE, SCREENING SERVICE AS TO RECEIVE A A OR B RECOMMENDATION FROM U.S. PREVENTIVE SERVICES TASK FORCE. IN COB TRASS TO THE TREATMENT OF THIS TOPIC AND AFFORDABLE CARE ACT, MEDICARE IS NOT REQUIRED TO COVER THINGS BASED ON ARC OR B RECOMMENDATION. THAT AUTOMATIC REQUIREMENT APPLIES TO PRIVATE HEALTH PLANS. THE SECOND CRITERION WE HAVE IS THAT IT HAS TO BE REASON BLUETOOTHABLE AND NECESSARY. FOR THE ACTUAL SCREENING. IT NEEDS TO ACTUALLY WORK. THE THIRD IS IT HAS TO BE APPROPRIATE PERSONS ENTITLED TO BENEFITS UNDER THIS TITLE. WHAT THAT GETS TO IS THIS, WHEN ONE IS DEALING WITH OR TASK FORCE I DON'T SPEAK FOR THEM BUT PEOPLE WHO DO THIS SPEAK ABOUT SCREENING REGIMES, THEY DEAL WITH LIFE EXPECTANCY, TOLERABILITY OF INTERVENTIONS APPROXIMATE THINGS ALONG THOSE LINES. A THERAPEUTIC INTERVENTION, THERE'S AN EARLY COST IN TERMS OF MORBIDITY AND MORTALITY ESPECIALLY IF INVASIVE AND YOU NEED TO LIVE LONG ENOUGH TO RECOUP THAT, INCREASE LIFE EXPECTANCY. SO WE ARE MINDFUL THAT'S SPECIALLY IN OUR POPULATION, EITHER IF TOLERABILITY OF CERTAIN INTERVENTIONS FRANKLY ISN'T THE SAME IN A 70-YEAR-OLD AS A 20-YEAR-OLD AND THE LIFE EXPECTANCY OF 20-YEAR-OLD IS SIGNIFICANTLY LARGER, BUT THAT'S OUR CONSTRUCT. >> FOR DR. JACQUES AS WELL, COULD YOU SUMMARIZE QUICKLY ANY CURRENT STATUS O COVERAGE WITH EVIDENCE DEVELOPMENT, WHAT THE RULES ARE? >> INSURE. COVERAGE OF EVIDENCE DEVELOPMENT IS A PARADIGM THAT THE AGENCY BEGAN TO ARTICULATE IN THE EARLY 2000s, AND DIDN'T REALLY FULLY ARTICULATE UNTIL 2006. IT IS ESSENTIALLY SAYS THAT THERE ARE SOME TECHNOLOGIES THAT ARE PROMISING BUT YOU DON'T HAVE CONCLUSIVE EVIDENCE OF BENEFIT. tj DEAL WITH THINGS LIKE THAT. WHAT WE HAVE DONE IS CONDITIONED TO COVERAGE ON ADDITIONAL CLINICAL EVIDENCE SUBMISSIONS, SOMETIMES THAT MAYBE REGISTRIES, SOMETIMES THAT'S FULL BLOWN CLINICAL TRIALS, DEPENDS THE OUTSTANDING EVIDENTIARY QUESTIONS AS WELL AS WHAT WOULD BE THE APPROPRIATE METHODOLOGY TO CONCLUSIVELY ACTUALLY ADDRESS THOSE QUESTIONS. WE STILL DO COVERAGE WITH EVIDENCE DEVELOP. >> LET MANY GET THE BALL ROLLINGENING A DIFFERENT DIRECTION. THIS MORNING WE HAD PRESENTATIONS FROM A NUMBER OF CLINICAL EXPERTS WHO OUTLINED NEEDS SOME CALL HI PRESENTED WISH LISTS. THEN WE HAD A PANEL OF EXPERTS IN A NUMBER OF DIFFERENT MODALITIES, IN THE TERMS OF THINGS THAT THEY FELL THEY COULD -- THEIR MODALITIES COULD OFFER. AND THEN WE HAVE HAD SOME PERSPECTIVE AS TO WHAT THE BARRIERS AS WELL AS RESOURCES ARE FOR THE POTENTIAL TRANSLATION OF SUCCESSFUL AGENTS. WHAT I WOULD LIKE TO GET IS SOME DIALOGUE GOING ON AS TO WHETHER -- WHERE ARE MATCHES BUT MORE IMPORTANTLY WHERE ARE MISMATCHES BETWEEN THIS IS WISH LISTS BETWEEN WHAT THE CLINICAL NEEDS ARE AS PERCEIVED BY CLINICAL EXPERTS BETWEEN -- OPPOSED TO WHERE THE PROBLEMS ARE BEING DEVELOPED. BECAUSE AT LEAST WHERE I'M SITTING I DON'T SEE A TERRIBLY GOOD HAND SHAKE BETWEEN WHERE I'M SEEING THE WISH LIST BETWEEN THE CLINICAL NEEDS AND WHERE THE PROBES MAYBE ARE BEING DEVELOPED. SEE WHETHER WE CAN SEE A PATH OF MORE EFFICIENT USE OF OUR RESOURCES TO PROBES BEING DEVELOPED WHERE EXPERTS TELL US THEY NEED THEM AND PERHAPS THEN ENGAGE PEOPLE IN THE OTHER AGENCIES TO SEE WHERE WE CAN MOVE THEM FORWARD TO CLINIC. SO WHOLE LIKE TO START? (OFF MIC) >> IF AN IMAGING AGENT BECOMES COMMERCIALLY VIABLE IT HAS TO BE BROAD. EVEN A BROAD BASED WITHIN ARE MARGINALLY VIABLE. THEY ARE USE ONCE OR TWICE WHEREAS YOU TAKE AN ANTIHYPE TENSIVE DRUG OR LIPITOR EF DAY FOR THE REST YOUR LIFE. IF IT'S AN ORPHAN DRUG INDICATION, A THERAPEUTIC YOU'LL BE TAKING IT THE REST YOUR LIFE. IF IT'S DIAGNOSTIC YOU HE WILL HAVE IT ONCE. SO PART OF THE BIGGEST PROBLEM HERE IS NOT THAT WE'RE NOT CREATIVE ENOUGH AND KNOW WHAT WE NEED BUT THERE'S NO RELIABLE WAY THE GET THESE INTO COMMERCIALIZATION BECAUSE YOU CAN'T MAKE A PROFIT AT ALL AND COMPANIES ARE OBLIGATED TO AT LEAST BREAK EVEN IF NOT MAKE A PROFIT. HA IS A PROBLEM FOR AGENTS IN GENERAL. IF THEY'RE COUPLED WITH A SPECIFIC THERAPEUTIC YOU HAVE A BETTER CHANCE. I THINK LOU CAN TALK THE THAT PART. BUT A GENERAL THING THAT MIGHT BE USEFUL IN A FEW HUNDRED PEEP, THAT'S NO PATH TO DEVELOP THAT. >> ANYONE ELSE HAVE SOME THOUGHTS ON THAT? >> (INAUDIBLE) FROM NCI AGAIN A. FOLLOW-UP QUESTION. THERE ARE ORPHAN DRUGS ORPHAN IMAGING AGENTS, IN THE CONTEXT OF THERAPEUTICS ARE THERE ARE 8 AGENTS THAT ARE USEFUL TO A SMALL NUMBER OF PEOPLE WITH WITH SAY A GENETIC DISORDER. I'M NOT AWARE BUT IS THERE A SIMILAR SITUATION IN THE IMAGING FIELD ARE A SMALL NUMBER OF PEOPLE MAY BENEFIT FROM DIAGNOSTIC -- THAT'S NOT DEVELOPED? >> THERE IS ALSO A PROVISION FOR WAIVING SOME OF THE FEES LIKE THE APPLICATION FEES, IF THERE ARE SPECIFIC REQUIREMENTS IN TERMS OF WHAT -- HOW LARGE AN INDUSTRY YOU ARE, WHAT YOUR PREVIOUS INCOME HAD BEEN. THERE'S OTHER FEES THAT ALSO CAN BE RECKON SENTENCED, THERE IS SOME MEASURE OF Ö IF YOU WILL, HELP IN TERMS BUT THE DRIVER THE MARKETING THE COMMERCIAL INSINTIVES. >> THE OTHER COMMENT THOUGH IS THE FDA FOLKS RESENTENCELY PUT TOGETHER A GUIDANCE FOR SPECIFICALLY FOR PET ON INDs, THAT DIDN'T HAVE ANY NEW LAW IN IT BUT IT PUT IT TOGETHER I THINK FOCUSED ON THIS INDUSTRY. THAT GIVES YOU WAY TO DO AN EXPANDED ACCESS IND. YOU CAN'T MAKE A PROFIT HOWEVER, THE INDICATION IF YOU HAVE 7 HUP PEOPLE IN THE WORLD WITH THE DISEASE, THAT'S ABOUT SOW ROW APPROACH. NO WAY TO GET A COMMERCIAL ENTITY TO TAKE THAT ON. SO WE HAVE HEARD ONE SUGGESTION WHY WE MAY HAVE 5,000 PROBES IN THE DATABASE AND VERY FEW MAKING THROUGH REGULATORY APPROVAL, DO ANY OF YOU HAVE OTHER PERSPECTIVES WHY WE HAVE THAT DEPRESSING SITUATION? OTHER THOUGHTS? MATCH OR MISMATCH BETWEEN THE WISH LIFT LIST FROM THE CLINICAL EXPERTS AND WHAT THE DEVELOPERS ARE DOING? IS THERE A DISCONNECT BETWEEN THE CLINICAL NEEDS AND WHAT DEVELOPERS ARE DOING? IF THAT'S THE CASE THEN WE HAVE A PROBLEM. UP FRONT. (OFF MIC) (OFF MIC) >> THANK YOU. THAT'S AN IMPORTANT PERSPECTIVE. YOU GET THE SAME EFFECT IN SOME OF THE ONCOLOGY THINGS BECAUSE I MIGHT BE ABLE TO DO SOMETHING LIKE FLT TO SAY THIS DRUG IS NOT WORKING IN THIS PATIENT. BUT THE ONCOLOGIST SAYS THAT'S MY LAST CHOICE, I'M GOING TO CONTINUE ANYWAY THOUGH THEY'RE ALL GOING TO GET SIDE EFFECTS AN ONLY 10% APPROVE. THIS IS MY ONLY CHOICE SO IT DOESN'T HELP KNOWING FROM THE MEDICAL TREATMENT POINT OF VIEW, THE PATIENT MIGHT DECIDE -- BUT THAT WOULDN'T BE REIMBURSED. ANY THOUGHTS OR CONSTRUCTIVE SUGGESTIONS HOW WE CAN REALIGN THINGS BETTER ALIGN IN THE DIRECTION OF DEVELOPMENT AND THE NEEDS? >> IT'S ALSO IMPORTANT TO HAVE AN IMPARTIAL BROKER WHO CAN (INAUDIBLE) PRIORITIES AND NOT SURE WHO THAT PERSON WOULD BE BUT IT WOULD SEEMS TO ME IN THE FACE OF SO MANY POTENTIAL CANDIDATES, EACH OF WHICH HAS SOME PROPONENTS THERE NEEDS TO BE AT SOME POINT SOME PROCESS OF PRIORITIZING THAT FOCUSING ON SPECIFIC PRODUCTS OR TARGETS AND SOMETHING ANALOGOUS TO WHAT INDUSTRY DOES, THEY HAVE CANDIDATES AND THEY SORT OF MAKE DECISIONS BASED -- THEIR DECISIONS ARE BASED ON MARKET FORCES. BUT I'M SURE SOME SIMILAR DECISIONS COULD BE MADE IN TERMS OF UTILITY OR THE NEED TO FOCUS ON SOME CANDIDATES THAT HAVE THE BEST OPTION TO BE TRANSLATED (INAUDIBLE). >> ANY -- SO THIS IS DRIVEN BY ACADEMIC DESIRE FOR MY PRODUCT OPPOSED TO YOURS. RIGHT NOW THERE'S TWO MAJOR GROUPS LOOKING AT GAL YUM (INAUDIBLE) FOR NEUROENDOCRINE, THEY SEEM TO BE -- REASONABLY EQUIVALENTLY EFFECTIVE BUT EACH GROUP IS PROCEEDING WITH THEIR OWN. THIS DOESN'T GET YOU TO A APPROVABLE DRUG. I DON'T KNOW THINKENING MAYBE SAYING NEURAL -- >> IF ONE LOOKS AT CMS AND FDA, WE OVER THE LAST COUPLE OF YEARS LAUNCHED A COUPLE OF INITIATIVES AROUND THE DEVICE CENTER, ONE IS THE REVIEW PILOT. THE OTHER ONE IS PRINTED RULE MAKING THAT WE HAVE NOW. TO CLARIFY CMS SUPPORT THROUGH MEDICARE PAYMENT THROUGH THE INVESTIGATIONAL DEVICE IN CATEGORY THE IDE TRIALS OUR ENGAGEMENT ON THE DRUG BIOLOGICS SITE IS DIFFERENT FOR A NUMBER OF REASONS. ONE MOST DRUGS ARE SELF-ADMINISTERD DRUGS. THEY DON'T COME TO OUR PART OF MEDICARE ANYWAY. AND MANY OF THE OTHER DRUGS ARE BIOLOGICS THAT FEATURES THE MARKET HAVE SMALLER SEGMENTS WITHIN THE POPULATION. IT MAYBE FOR ARTHRITIS AN WE ARE' HAPPY TO LET THE LOCAL CONTRACTORS DEAL WITH THOSE THINGS. BUT THE REALLY BIG DRUG THAT EVERYBODY TALK ABOUT POSTALLY ARE ORAL DRUGS. WE WON'T DO A NATIONAL COVERAGE DETERMINATION ON LIPITOR, IT WILL BE LATE TO START ONE, BUT IT'S A PART D DRUG, WE DON'T DO NATIONAL COVERAGE DETERMINATIONS ON PART D DRUG SO OUR ACTIVITIES ARE MORE LIMITED. ON THE DEVICE SIDE WHAT WE LAID OUT THERE, NOT FORMAL BUT INFORMALLY THAT IF SPONSORS WANT TO COME AND EITHER I HAVE BEEN SITE CMS TO THEIR FDA MEETING PRE-IDE MEETINGS, WHATEVER MEETINGS WE ARE MORE THAN WELCOME TO COME. WE WILL COMMENT, LET THEM KNOW YOWIE IN THE BALLPARK YOU'RE NOT IN THE BALLPARK, ARE WE ENTHUSIASTIC BASED ON HOW YOU DID YOUR TRIAL, DEVICE TRIAL VERSUS YOUR OWN CHALLENGES NOT INFERIORITY TRIALS, NON-INFORMATIVE TRIALS. BUT WE ARE OPEN TO THOSE CONVERSATIONS, ALSO WE'RE OPEN TO THE CONVERSATIONS TON THE DRUG SIDE BUT AS MOST DRUGS DON'T COME TO US, MAYBE MEDICARE MIGHT WANT TO SEE OUR PROTOCOL. AT NIDDK IMAGING HAS TO DO WITH PERSONALIZED MEDICINE, DIFFERENCIAL DIAGNOSIS IN OUR PATIENTS TO TRY TO INFLUENCE THERAPY TO TYPE IT UP A LITTLE BIT. HOW DOES CMS LOOKING AT FUTURE OF PERMIZED MEDICINE? >> EASY QUESTION. YEAH. THERE'S A COUPLE OF ISSUES AROUND PERSONALIZED MEDICINE SOMETIMES USE ZED AS UMBRELLA TO TALK ABOUT EVERYTHING FROM MOLECULAR DIAGNOSTICS TO OTHER THINGS. ON THE DIAGNOSTICS SIDE WE HAVE THE MALDEX PLAN FROM CONTRACTOR TO TRY TO EVEN GET CLARITY WHAT MEDICARE IS PAYING FOR. MOLECULAR DIAGNOSTIC CLAIMS ARE SUBMITTED STACKING CODES. THE MEDICARE PROGRAM HAD NOI KNOW WAY OF KNOWING WHAT EXACTLY THE TEST WAS. SO THREE ALLOQUATS OF SPECIMEN COLLECTION, CALM OF COLUMNS, THIS, THAT, A GEL AND SOMETHING ELSE AND IT WAS BILLED AS INGREDIENT. YOU WENT TO A YOURRY STORE, IN THE BAKERY SECTION WHAT YOU GOT WAS FLOWER, BABING SODA, POWDER YEAST, WHATEVER BUT YOU DON'T KNOW WHETHER YOU'RE BUYING A CROISSANT, YOU DONE ORDER A ICE CREAM SANDWICH. THAT'S THE WAY MEDICARE DWELT THINGS FOR DECADES BECAUSE THERE WAS NO ALTERNATIVE,K SEE A PAPER OR BUYER WOULD BE UNENTHUSIASTIC ABOUT BUYING A UNLABELED TAG OF INGREDIENTS. WE'RE GETTING MORE CLARITY AROUND THAT NOW. ONE CHALLENGE WE FACE IN PERSONALIZED MEDICINE IS RELATED TO FACTOR UNIQUE TO OUR BENEFICIARY POPULATION LOOKING SPECIFICALLY AT DIABETES, TYPE 2 DISEASE RATHER THAN TYPE 1 DISEASE, CHEERILY THEY'RE DIFFERENT DISEASES. THERE IS A FAIR EVIDENCE BASE THAT'S STARTING TOY A CUMULATE WHETHER IT'S PARTIALLY FROM A COURT OR WHETHER IT'S FROM OTHER STUDIES IF YOU TAKE OUR TYPICAL BENEFICIARY AND TRY TO TIME TIGHTLY CONTROL THEM YOU IN FACT KILL THEM RA THEY WERE SAVE THEM. SO THERE ARE FOLKS FOR EXAMPLE (INDISCERNIBLE) AT THE VA WHO SAID ONE TIME IN A PRESENTATION IF YOUR LIFE EXPECTANCY IS LESS THAN TEN YEARS YOU'RE UNLIKELY TO ACCRUE SIGNIFICANT BENEFIT FROM AGGRESSIVE GLUCOSE MANAGEMENT, YOU'RE MORE LIKELY TO HARM YOURSELF FROM THE ADVERSE EVENTS OF LOW GLYCEMIA, FALL, BREAK A HIP, ET CETERA, ET CETERA SO FOR US IT'S REALLY COMPLICATED. (OFF MIC) >> WE WERE NOT TACKING THE SAME THING, WE WERE TALKING ABOUT A COMPOUND EVALUATING THE WAY BETWEEN 10, 20 PEOPLE, >> IT'S MATTER OF RADIO PHARMACEUTICAL VERSUS NON-RADIO PHARMACEUTICAL. AND RAID YES PHARMACEUTICAL YOU HAVE THE TRACER PRINCIPLE, MICRODOSING, ET CETERA, IT'S AN OPTICAL AGENT, YOU HAVE TO GIVE TEN MILLIGRAMS IT'S A WHOLE DIFFERENT (INAUDIBLE) THAT GETS THINGS UP MORE THAN 1 MILLION. I THINK YOU HAVE RADIO TRACER YOU CAN DO FOR LESS THAN 1 MILLION DOLLARS, 12 PATIENTS. ONE SPECIES ACUTE SUBACUTE TOXICITY, THE IND ISN'T THAT HARD TO WRITE. BUT IF YOU WANT A NANOPARTICLE, ONE MULTI-FUNCTIONAL AGENT, THOSE ARE VERY DIFFICULT. AND THAT'S JUST FOR PHASE 1, YOU WANT PHASE 2 WITH RADIO PHARMACEUTICAL, I ARGUE EVEN THAT PROBABLY APPROACH APPROACH THE DOUBLE DIGIT. BUT GETTING BENEATH HUMAN SKIN YOU CAN DO RADIO TRACER. YOU GUYS SPECIFICALLY HAVE TO DECIDE 'ALLY THE NICE PROGRAMS ARE DOING THAT BUT BEYOND THAT, IT'S AL CHALLENGING. I'LL ADD TONA IN TERMS OF EXPANDING FROM IND TO PREVIOUS LIFE I CAN SAY YOU'RE UPWARDS OF ANYWHERE FROM 5 TO $15 MILLION >> ON THE OTHER HAND YOU CAN GET A LIFE DOSE (INAUDIBLE) WHICH IS OLD,'S PLENTY OF DATA IN THE LITERATURE, LOTS I HAVALS TO DO NATURAL THINGS OR ALREADY CLOSE, YOU CAN OFTEN GET THOSE INTO PHASE 1, PHASE 0 TRIAL WITH ALMOST NO TOXICOLOGY. YOU HAVE TO MAKE A GOOD CASE. IT HAS TO BE GOOD SCIENCE, IT'S GOT TO BE REASONABLE AND YOU HAVE TO SAY -- ADDRESS THE RISK. BUT DEPENDS ENTIRELY HOW MUCH APPROXIMATE WHAT IT IS. IF YOU'RE TAGGING THAT ANTIBODY WITH SAID A RADIONUCLIDE THAT'S EASY TO GET TO TOO. BECAUSE YOU CAN USE THE TOXICITY TESTING THAT THEY PHARMACEUTICAL COMPANIES ARE ALREADY DONE AND THEN DO DOSIMETRY AND NOT GETTING RADIATION DOSE THAT'S UNACCEPTABLE. THERE ARE A NUMBER OF CLINICAL TRIALS THAT ARE DONE WHICH MAYBE UNDERPOWERED FOR WHICH THERE MAY NOT BE ADEQUATE CHARACTERIZATION OF THE PRODUCT. SO MORE THOUGHT COULD GO INTO DEVELOPING STANDARDS. I DON'T KNOW WHETHER IT COULD BE PUBLICATIONS OR SOCIETIES THAT COULD DEVELOP SOME OF THESE. TO HAVE AN EYE TO MORE, NOT AN FDA INSISTS CLINICAL TRIALS BUT IF YOU YOU HAVE A PUBLICATION THERE SHOULD BE WAY OF UNDERSTANDING WHETHER BIAS WAS AVOIDED, WHETHER RANDOMIZATION WAS DONE, WHETHER CLINICAL SAFETY WAS COLLECTED. SO THERE'S POTENTIAL OF SEEKING APPROVAL BASED ON PUBLICATION. THERE ARE INSTANCES WHERE WE DON'T REQUIRE PRIMARY DATA SO STANDARDIZING AND MAYBE I WOULDN'T SAY PROVING THE QUALITY BUT MAKING THE PUBLICATIONS MORE CONDUCIVE TO PROVIDING THE ELEMENTS THAT THE FDA NEED TO ASSESS THE CALL OF THE DATA. COULD GO A LONG WAY TOWARDS -- >> I WAS LOOKING TO DO THIS WITH FLT AND I DID A MASSIVE LITERATURE REVIEW. 99% SAID NOTHING ABOUT SAFETY. I DEDUCED THEY MONITORED BECAUSE THEY SAID I WENT TO IRB ORETH HEALTHCARES COMMITTEE. HALF DIDN'T TELL ME SPECIFIC ACTIVITY OR MASS OR ANYTHING RELATED TO THAT. MOST GAVE ME THE DOSE IN RADIATION. THAT'S IT. NO WAY I CAN DO A META ANALYSIS ON THAT. EVEN IF IT WAS THE IDENTICAL POPULATION. THEY DIP TELL ME HOW THEY MADE IT OR WHAT THEIR SPECIFICATIONS WERE. NO I DON'T KNOW THEY WERE THE SAME THING. THAT'S AN ISSUE THAT CAN BE DEVELOPED I THINK BY SIGN ACTIVIC SOCIETY. >> JUST ON THAT NOTE I AGREE ENTIRELY. AND THIS HAS BEEN HANDLED AT LEAST BY SNMMI AT THE JOURNAL OF NUCLEAR MEDICINE SO IF YOU MAKE A REPORT ON A NOVEL IMAGING AP GENERAL YOU NEED THE TO SPECIFY MASS DOSE THAT WAS ADMINISTERED AND YOU NEED TO COMMENT ON THE PRESENCE OR ABSENCE OF ANY OBSERVABLE AFFECT LET ALONE ADVERSE ONE. IF MORE JOURNALS SUBVISING PUBLICATIONS THIS OUR AREA MAY THOSE REQUIREMENTS AND EXTENDED TO SECONDARY AN TERTIARY REPORTS OPPOSED TO JUST THE FIRST REPORTING AGENT YOU WOULD HAVE THE DATA YOU NEED. >> THEN WE CAN DO IT AND IT'S EASY WITH JOURNALS WITHING SUPPLEMENTARY INFORMATION. SO ONE THING THAT PERHAPS SCIENTIFIC SOCIETIES LEAD WITH IS DEVELOPING JUST A LIST OF WHAT DO I WANT TO KNOW LIKE THAT, AND SAYING YOU SHOULD PUT THIS IN AND PUT ANYTIME THE SUPPLEMENT AND WE'LL BE ABLE TO WITH LONG DEVELOPED LOW USE AGENTS DEVELOP PAPER NDAs. >> SINCE DATA ARE NOT PROPRIETARY WE VALUE THE ABLE TO GO BACK AND LOOK AT THE PRIMARY DATA SO IF THAT HAS NO COMMERCIAL VALUE IT COULD BE MADE AVAILABLE AS PART OF PUBLICATION THAT COULD ALSO BE USEFUL. FROM >> IF THERE ARE NO OTHER QUESTIONS SEEMS LIKE WE EBBED UP A VERY CONSTRUCTIVE NOTE. ON BEHALF OF NIBIB LET ME THANK ALL OR SPEAKERS FOR A VERY INFORMATIVE VERY PRODUCTIVE WORKSHOP. [APPLAUSE]