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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
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
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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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
26N THE JOURNALOF NUCLEARMEDICINE«Vol. 40 •No. 7 •July 1999
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