Pharmaceutical Discovery And Development: Nuclear And Molecular ImagingTechnologies Recognized

"Like my col

leagues in

SNIDO, I

wanted to do

something

about the

great com

munication

gap between

academicians

and pharma

ceutical

researcherswho don't

know what

the other sidecan offer."

A small volunteercoalition is workinghardtopropelthe futuredevelopmentofnuclearimaging technologies. The Society of

NuclearImagingin DrugDevelopment(SNIDD)was founded in 1991 with a singularly ambitiousmission—toeducateacademia,industryandthe regulatory community on how partnershipsto developandapplynuclearandmolecularimaging technologies can streamline the process ofdrug discovery and approval.Only a small committee at its inception, SNIDD is now gaininginternational visibility and support as imagingresearchersstarttodemonstratenewwaysto attackR&D challenges and sow the seeds of futurecollaborations. Of SNIDD's 80 members, about

a third each come from academia, industry,andgovernment.

"By the early90s,pressureson the drug indus

try to become more efficient increased substantially, and the potential role of PET (especiallyincentralnervoussystemdrug research)wasgetting seriousconsiderationby severalPETcentersanda smallnumberofdrugcompaniesasonewayof accomplishing this," said Donald Burns,

PhD,MerckResearchLaboratories,formerexecutive committee chair and current SNIDD treasurer. "As a result, we saw the need to begin

havingregularmeetingsandsymposiaonthesubject and to recruit interested volunteers to helpwith these programs."

StrongcommercialsupporthasenabledSNIDDto sponsora diverseeducationalprogramthat features international workshops and meetings(including a major meeting at NIH in September 1998) and an online directory of PET centers (see " SNIDD on the Internet,"accompany

ingthisarticle).ThisSeptember,twoback-to-backworkshops in Amsterdam and Paris will informscientistsandpharmaceuticalrepresentativesabouthigh-resolutionsmall-animalimagingmodalitiesand their applications to drug development,neuroscienceand molecularbiology.Inaddition,a four-day satellite vidéoconférencecourse atLehighUniversitywillbringtogethersubscribersfrom industry and the FDA learn about applications of PET and SPECT to current drug development problems.Althoughtheorganizationhasno regulatorymission,representativesfrom FDAhavealsoparticipatedinotherSNIDD-sponsored

meetings. SNM also holds a prominent placewithin SNIDD ranks. "Members of SNM repre

sent a huge reservoir of expertise in applyingnuclear and molecular imaging technologies toreal drug development questions," said Richard

Frank, MD, PhD, senior director of exploratorymedicine at Sanofi-WinthropUSA and SNIDDpresident. "SNIDD-sponsored workshops and

seminarsalwaysincludeSNMspeakers,whomakeup a good proportion of our leadership as well."

The close association between the two societiesenabled the SNM Radiopharmaceutical Council to sponsor a categorical seminar at the June1999 SNM Annual Meeting entitled "Neu

roimaging: A Tool for Neuropharmacology andDrug Discovery," at which Frank spoke about

businessand regulatoryperspectiveson the valueof nuclear and molecular imaging technologies."Like my colleagues in SNIDD, I wanted to do

something about the great communication gapbetween academicians and pharmaceuticalresearchers who don't know what the other sidecan offer," said Frank. "Ten years ago, I first

became aware of the tremendous drug researchpotentialof PET when Iparticipatedinone of thefirst clinical trials that applied PET in conjunctionwitha receptor-specifictracerto a drug development problem. By quantifying receptor saturation of a labeled serotonergicagent, we coulddirectly measure how much of the agent crossedtheblood-brainbarrierduringa phaseIItrial.Several investigatorsare nowsimilarlyapplyingPETin new ways to research treatments for cancer,Parkinson's disease, and rheumatoid arthritis.

As liaisons between industry and academia,SNIDD members can be effective educatorsand advisors in bringing together the right partners to greatly expand these efforts."

The typesof collaborationsthat SNIDDworksto fosterare science-driven,but the businessspinhas become even strongerin the past eight years."SNIDD was founded on the idea that our sci

entific mission to acquire new radiopharmaceu-ticals and imaging systems is tied to getting themessage across that these technologiescan meetthe demands for faster screening and approvalof investigational compounds," said Timothy J.

McCarthy, PhD, assistant professor of radiology,WashingtonUniversityMedicalSchool,who

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Adenovirus Directed Gene Expression of theD2 Reporter Gene in Liver

Mouse Model PET Reporter Probe: [F-18JFESP

Control

TherapyGene

PETReporter

Gene

VirusVehicle

Using a PET reportergene/reporter probe toimage and measurethe location anddegree of expressionof a therapy gene, orany other transportedgene, to alter cellularfunction. PET reportergene traces therapygene because theyshare a commonpromoter

servesas SNIDDsecretaryandnewsletterco-editor and is also co-organizer of the SNM seminar.Whilethe message is still fairlynewto manyoutside of SNIDD, the goals that these technologies can help to meet have become universal, added Frank. "In just a few years, a coales

cenceof regulatory,scientificandbusinessfactorshas created a situation where government andindustry cannot afford to overlook the dramaticadvances in imaging technologies, particularlyPET technologies. The FDA has streamlinedthe approvalprocess by allowinga singlephaseIII study to support efficacy, while at the sametime, pharmaceutical companies are starting tolookfor cost-effectivemethodsto screenthenewmolecular targets and active substances that arenow floodingthe market as a result of advancesingenomics,proteomics,andcombinatorialchemistry."

In vivo quantificationof biological processesto measure an agent's mechanism of action and

its concentration at the site of action is, consequently,becomingabusinessimperativefordevelopinga drug."A criticaltimeandcostadvantage

for the pharmaceutical researcher in partneringwith a nuclear imaging program is to be able tomore efficiently identify compounds that canactuallymodify disease processes and that havesuitablepharmacokineticandpharmacodynamicprofiles," explained Simon Cherry, PhD, asso

ciate director of the Crump Institute for Biological Imaging and associate professor, Department of Molecular Pharmacology,UCLA, whois co-organizing the upcoming satellite video-

conference."By gain

ing access to PET,SPECT or planarnuclear imaging, apharmaceuticalresearcher has thepowertoradiolabelthedrugitself,quantifyitsabilityto reachtargetsof interest throughbinding and occupancystudies,ormeasure its effect on biological systemsthrough measures ofmetabolismandbloodflow." On the other

side of the equation,said McCarthy,academic scientists whopartner with pharma

ceutical companies producing investigationalcompounds gain access to new lead compoundswith which to develop novel radiopharmaceuti-cals. "Developing new radiopharmaceuticals to

target specific biochemical processes can leadto newclinicalresearchcollaborationswithintheinstitution.For instance,our research group hasevaluated a fluorinated derivative of captopril,which we hope can be used to assess the role ofangiotensin-converting enzyme in pulmonaryhypertension."

Theviabilityof suchpartnershipsdependsmoston ongoingimprovementsin and increasedavailabilityof advancedPET technologies,explainedFrank. "PEThascomeintosharperfocusforboth

academia and industry as we realize that it canprovide confirmational data and support thelogicalprogression from phase I to phase III trials,as wellasestablishbiomarkersof disease.Assuch, validationof new model imaging systemsthatuse PET,inparticularsmall-animalscanning,will provide a bridge within the pharmaceuticalindustry between preclinical drug developmentscientistsand cliniciansrunningphase I to III trials." Industry and academia are starting to forecast that small-animalPET scanningwill surpassthe limitsof currentnuclear imagingtechnology,addedCherry."The FDAhasalso recognizedthe

potential value of micro-PET modalities and isnow encouraging collaborations while standingback to seehowtheseapplicationswillbear out."

By June 1999, the Crump Institute and theMallinckrodtInstituteof Radiologywill acquire

(Continued on page 26N)

Newsline 23N

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mine treatment for their patients."

While it is true that nuclear physicianswho work at a cancer center may havean easier time integrating into a specialty beyond nuclear medicine, nuclearphysicians at broader-based hospitals

can still apply the techniques used atSloan Kettering to their own practices,according to Macapinlac. For instance,a nuclear physician can focus on sportsmedicine and set up a team with orthopedics, while another can focus on cardiology and create links with the cardiac care unit. In fact, Wagner takes thisconcept one step further: He said hebelieves that the disintegration of thetraditional nuclear medicine departmentand the integration of nuclear medicineinto various specialties could be a veryreal possibility in the next millennium,at least at some institutions. "A nuclear

oncologist would have an oncologypractice and also perform lym-

phoscintigraphy, just like a nuclear car

diologist sees cardiac patients and performs perfusion imaging," he said.

Most nuclear medicine leadersbelieve, however, that nuclear medicinewill remain a separate entity unto itselfwith nuclear physicians maintainingbroad-based practices in nuclear med

icine or radiology. Still, the growingnumber of uses for nuclear medicine inmolecular imaging has ignited an excitement among physicians outside thenuclear medicine field. "The under

standing and knowledge of PET amongreferring physicians has increased dramatically over the last year or two," said

Coleman. He has experienced a significant increase in referrals for PETprocedures, especially after Medicarebegan to cover PET for certain indications. "Our department experienced a

30% increase in PET procedures from1997 to 1998, and we expect the increaseto continue this year," said Coleman. He

said he expects his department to per

form more than 2000 PET scans thisyear, compared to 1600 scans last yearand 1200 scans in 1997. Althoughnuclear physicians perform the scansand process all the data at Duke,researchers from various specialtieshave recently become more well-versed

in the intricacies of PET, according toColeman. "However, I don't see inte

gration of nuclear medicine with otherspecialties at this point," he said.

Only time will tell whether integrationis indeed the wave of the future. For thepresent, nuclear physicians can use onesimple assessment to determine whethertheir own discipline has become moreintegrated: Where is it located? "Our

department is located in a busy sectionof the hospital, not in the basement awayfrom everyone," said Macapinlac."Referring physicians want us in a con

venient location, so they can drop in ona regular basis and see our scans."

—Deborah Kotz

SNIDD(Continued from page 23N)two of the first eight commercially produced small-animal PET scanners, which

are copies of the prototype scanner developed by Cherry's research group (seeChatziioannou et al, "Performance Eval

uation of microPET: A High-ResolutionLSO PET Scanner for Animal Imaging,"

in this issue)."We originally built the prototype as

a physics challenge without really appreciating the wide range of applications.We now find we need a second systemhere at UCLA because the small-animal

scanner has become our most heavilyused PET machine," said Cherry. An

anticipated dividend of commercializing micro-PET that SNIDD emphasizes

is that the technology will provide a seamless transition from preclinical pharmacologie studies to phase I trials, saidMcCarthy. "At the early stage in drug

development, compounds are evaluated in small animal models. In manycases, these compounds may behave differently in higher species. PET provides

an opportunity to determine if these problems exist before developing a compoundfurther. Put another way, tremendous costsavings can be realized by being able tomake early decisions about a lead compound's suitability for further development."

Another anticipated benefit is thatmicro-PET will provide more sophisti

cated ways to utilize the many transgenicmouse models of disease that havebecome central to the drug developmentprocess, said Cherry. "With micro-PET,

we can repeat the same study on a singlemouse, which allows us to do very useful things such as monitoring the biochemical response to drugs as a functionof time. In the future we also believe thatwe will be able to monitor gene therapywith PET, providing us with a tool toassess new molecular therapies. Continued improvements in PET spatial resolution will in a year or so allow for moreprecise measurements of the biologiceffects of drugs on particular sets of cellsin the mouse. Perhaps within five yearsthese capabilities will be further enhanced

by building complete micro-PET sys

tems within CT or MRI machines in orderto combine precision functional andanatomical imaging."

Lack of communication and the current limitations of nuclear imagingmodalities are not the only challengesSNIDD faces in forging industry-academic partnerships, said Frank. "The inter

national pharmaceutical industry hasrecently concluded, very significantly,that no drug company can singularly ownthe new imaging modalities. Rather, thesetechnologies will remain in the publicdomain and drug companies will compete on a drug-by-drug basis. Still, the

proprietary nature of molecules andimaging systems patented by a pharmaceutical company will have to be considered by its academic partners whowant access to these resources." Another

challenge, added McCarthy, will be totry to standardize the way in which validation studies of new radiopharma-ceuticals are carried out among the radio-

pharmaceuticals research community.—JillKatz

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1999;40:22N-26N.J Nucl Med.   Jill Katz  Technologies RecognizedPharmaceutical Discovery And Development: Nuclear And Molecular Imaging

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