CONCLUSIONThese studies suggest:

1. Various enzymes catalyze the hydrolysis of 9@Tc-ECD,and the enzymatic systems are different between tissuesand between species.

2. pH has little effect on 99mTc@ECD metabolism in thebrain.

3. There are regional differences in intracranial metabolicactivity in cynomolgus monkey.

4. In both rat and cynomolgus monkey tissue, metabolicactivity is low in blood, intermediate in brain and high inliver.

It remains to be determined whether regional differences inmetabolic activity in the intracranial tissues influence 9@°@TcECD SPECT images.

REFERENCESI. Moretti JL, Caglar M, Weinmann P. Cerebral perfusion imaging tracers for SPECT:

which one to choose? J Nuci Med 1995;36:359—363.

2. Leveille J, Demonceau G, De Roo M, et al. Characterization of technetium-99m-L,L-

ECD forbrainperfusionimaging,part2: biodistributionandbrainimagingin humans.J Nuci Med l989;30:l902—1920.

3. Walovitch RC, Hill TC, GaITityST, et al. Characterizationof technetium-99m-L,L-ECD for brainperfusionimaging, part I: pharmacologyof technetium-99mECD innonhuman primates. J Nuci Med 1989;30:1892—l9Ol.

4. Walovitch RC, Franceschi M, Picard M, Ct al. Metabolism of @mTc.L,L@ethyl

cysteinate dimer in healthy volunteers. Neuropharmacology 1991 ;30:283—292.5. Walovitch RC, Cheesman EH, Maheu U, Hall KM. Studies of the retention

mechanism of the brain perfusion imaging agent, @“Tc-bicisate(@“Tc-ECD).JCereb Blood Flow Metab 1994;14(suppl l):S4—SII.

6. Holmes R5, Masters CJ. The developmental multiplicity and isoenzyme status of

cavian esterases. Biochem Biophys Acta l967;132:379—399.7. Bormans G, Van Nerom C, 1k Beukelaer C, Hoogmartens M, De Roo M, Verbruggen

A. Comparisonof @“Tc-ECDmetabolismin organ homogenatesof ratand baboon[Abstract]. Eur J Nucl Med 1989;15:423.

8. Yonekura Y, Nishizawa 5, Mukai T, et al. Functional mapping of flow and

back-diffusion rate of N-isopropyl-p-iodoamphetamine in human brain. J Nuci Med1993;34:839—844.

9. Kawashima R, Koyama M, Ito H, et al. Normal cerebral perfusion of @“Tc-ECDbrain

SPECT:evaluationby an anatomicalstandardizationtechnique.Kakuigakul996;33:69—72.

10. Van Nerom C, BormansG, Dc BeukelaerC, Dc Roo M, VerbruggenA. Metabolismof @‘Tc-ECDin organ homogenates of baboon [Abstract]. Eur J Nuci Med1989; 15:423.

18FFPH at 130 mm was highlycorrelated with the known densitiesofnAChRmeasuredinvftroinhuman(r=0.81)andratbrain(r=0.90). Conclusion: These results demonstrate the feasibility ofimaging nAChRs in vivo. Fluorine-18-FPHappears to be a suitabletracerto studynAChRsin the humanbrain.Key Words nicotinic receptors; PET; nonhuman primate; brain;epibatidine

J Nuci Med 1997;3&1737—1741

INicotinicacetylcholinereceptors(nAChRs)havebeenimplicated in a variety of central processes, such as learning andmemory (1—4)and antinociception (5). These receptors alsomediate the reinforcing properties of nicotine in tobacco products (6, 7). The loss ofcholinergic neurons in the basal forebrainhas been associated with a variety of pathological disorders,such as senile dementia of the Alzheimer type, Huntington'sand Parkinson's diseases and progressive supranuclear palsy(8—15).

Neuronal nAChRs are ligand-gated ion channels composedof two kinds of subunits (a and (3) (1). There are at least threesubtypes of nAChRs in the central nervous system as identifiedby radioligand binding techniques (1, 16): (a) those with highaffinity for (-)-nicotine, which are labeled by agonists such as3H-acetylcholine and 3H-cytisine (nicotine/ACh) (1 7); (b) thosewith high affinity for ‘251-a-bungarotoxin(aBgT) (18); and (c)those that selectively recognize neuronal bungarotoxin (n-BgT)(19). The pharmacological profile of a receptor subtype isrelated to its subunit combination. There is a good correlationbetween the distribution of nAChRs with the a4@2 subunitcombination and the distribution of high-affinity nicotine/ACh

Nicotinic acetylcholine receptors (nAChRs)have been implicated ina varietyof centralprocesses,suchas learningand memoryandanalgesia.These receptors also mediate the reinforcing propertiesof nicotinein tobaccoproductsand are increasedin postmortemsamples of brains of smokers. On the other hand, brains of indMduais who have died from dementia of the Alzheimer type showabnormally low densfties of nAChRs. In this study, the distributionand kinetics of [(±)-exo-2-(2-r8FJfluoro-5-pyridyl)—7-azabicyclo[2.2.ljheptaneC8F-FPH),a high-affinitynAChRagonist,wasevaluated in a baboon using PET. Methods After intravenousinjectionof 5 mCi [185MBa] 18F-FPHinto a 25-kg anesthetizedbaboon, sequential quantitative tomographic data were acquiredover a period of 150 mm. Regionsof interestwere placedandtime-activitycurvesweregenerated.Brainkineticsofthe radiotracerwere calculated,and the in vivo regionalbinding in the baboon brainwas comparedwith the known in vitro regionaldistributionofnAChRs in the rat and human brain. Results: Brainactivity reacheda plateauwithin60 mmafterinjectionof thetracer,andthe bindingwas reversible. Elimination of 18F-FPH was relatively rapki from thecerebellum (clearancet1,@= 3 hO,intermediate from the hypothalamus/midbrain(t1,@= 7 hr)and slow from the thaIamus(t1,@= 16hr).Radioactivitydueto 18F-FPHat 130mmpostinjectionwashighestinthethalamusandhypothalamus/mkJbrain,intermediatein the neocortex and hippocampus and lowest in the cerebellum.Subcutaneous injection of 1 mg/kg cytisine 45 mm after injection of theradiotracer reduced brain activity at 130 mm by 67%, 64%, 56%and52%of controlvaluesinthethalamus,hypothalamus/midbrain,hippocampus and cerebellum, respectively. The regional binding of

ReceivedSep.12,1996;revisionacceptedDec.19,1996.Forcorrespondenceorreprintscontact:RobertF.Dannals,PhD,DMsionofNuclear

Medicine,The Johns Hopkins Medic@Institutions,615 North Wolfe St, Room 2001,Baltimore,MD 21205—2179.

IMAGING NICOTINIC RECEPTORS WITH PET •Villemagne et al. 1737

Imaging Nicotinic Acetylcholine Receptors withFluorine-18-FPH, an Epibatidine AnalogVictor L. Villemagne, Andrew Horti, Ursula Scheffel, Hayden T. Ravert, Paige Finley, David J. Clough, Edythe D. London,Henry N. Wagner, Jr. and Robert F. DannalsDivisions ofNuclear Medicine and Radiation Health Sciences, The Johns Hopkins Medical Institutions; and Brain ImagingSection, Intramural Research Program, National Institute on Drug Abuse, National Institutes ofHealth, Baltimore, Maryland

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. ‘8F-FPH PET Study

130 mm post injection,,@@

U-k

¶,@1m•FIGURE1. Blackand whitecodedtransformsof PETscansshowing18F-FPHbindinginthebaboonbrainat130mpi.Thereishighuptakeoftheradiotracerin thethalamusandhypothalamus/midbralnregions,intermediateuptakeinthefrontalcortexandlowuptakeinthecerebellum.

THA@t cB

HYP/MBA CB

LA AA

30 60 90

binding sites (20), between the distribution of a7 mRNA andaBgT high-affinity binding sites (18), and between cr3 mRNAand n-BgT binding sites (19).

Carbon-i l-methyl-(-)-nicotine has been used to studynAChRs in nonhuman primates, normal human volunteers (21)and patients with Alzheimer's disease (22) by means of PET.However, the high nonspecific binding and rapid clearance of[1 ‘C-methyl]-(-)-nicotine from the brain preclude the wide

spread use of this radioligand in the in vivo evaluation ofnAChRs in human subjects.

Epibatidine ((-)-exo-2-(2-chloro-5-pyridyl)— 7-azabicyclo[2.2.l]heptane), an extract of frog skin, is a potent alkaloid withantinociceptive properties and extremely high affinity fornAChRs in vitro (23—25).In vivo studies with [3H]epibatidinein mice showed high brain uptake of the tracer, a regionaldistribution consistent with that of nAChRs, a slow clearancefrom brain and low estimates of nonspecific binding (26). Thein vivo biodistribution of the [3H}norchloro analog was similarto that of the parent compound (27).

In this study, an in vivo characterization of the distributionand kinetics of (±)-exo-(2-['8F]fluoro-5-pyridyl)—7-azabicyclo[2.2. l]heptane (‘8F-FPH)(28) binding to nAChRs in thebaboon brain was performed using PET. To demonstratespecific binding to nAChRs receptors, the regional distributionand specificity of the binding were examined.

MATERIALS AND METhODSFor the PET procedures, a 25-kg male baboon (Papio Anubis)

was initially anesthetized with 8—10mg/kg alfadolone and alfaxolone acetate (Saffan®)intramuscularly and intubated. Anesthesiawas maintained throughout the study by a continuous intravenousinfusion drip of 6—9mg/kg/h alfadolone and alfaxolone acetate.

The baboon was then comfortably restrained to the PET bedusing an individually fitted thermoplastic mask that allowedreproducible positioning between studies. Pulse and oxygen saturation were continuously monitored during the studies. Bloodoxygen saturation was always maintained above 85%.

No-carrier-added (±)-exo-2-(2-['8F]fluoro-5-pyridyl)—7-azabicyclo[2.2.l]heptane (18F-FPH) and authentic (±)-exo-2-(2-fluoro5-pyridyl)—7-azabicyclo{2.2. 1}heptane (FPH) were prepared aspreviously described (28). Briefly, a solution of (±)-exo-2-(2-bromo-5-pyridyl)—7-azabicyclo[2.2. l]heptane in DMSO wasstirred with K (18)F/Kryptofix 222®complex for 15 mm at 200°C.The labeled product was purified by preparative high-performanceliquid chromatography. Chemical and radiochemical purities, determined by HPLC, exceeded 95%. Sterility and apyrogenicitytesting were performed using standard procedures. The averagespecific activity of the final product calculated at the end ofsynthesis was greater than 2000 mCi/p.mol. Authentic, unlabeledFPH, used as a standardin HPLC, was preparedby Kryptoflx®222-assisted nucleophilic fluorination of (±)-exo-2-(2-bromo-5-pyridyl)—7-methoxycarbonyl-7-azabicyclo[2.2.l]heptane followed byacid deprotection.

After the baboon was positioned in the PET scanner, a transmission scan was performed with a 68Ga source to allow forattenuation correction. PET scanning was started immediately afterintravenous injection of 5 mCi [185 MBQJ of high specific activity18F-FPH(corresponding to 0.12 nmol/kg); 15 simultaneous (eightdirect planes, seven cross planes, Z axis = 10 cm) sequentialquantitative tomographic slices of the brain were obtained with theGE 4096+ PET tomograph in the high-resolution mode (—6.5mmFWHM) over a period of 150 mm. The baboon was positioned sothat the lowest plane was located about 5 cm below the canthomeatal line. No blood samples to measure plasma radioactivitywere obtained. In a second study measuring displacement of

‘8F-FPHfrom nAChRS, 1 mg/kg of cytisine, a selective partialagonist at nAChRs (1), was injected intravenously 45 mm afteradministration of the radiotracer.

PET images were reconstructed from the raw data with astandard filtered backprojection algorithm and a Hann filter (6.0mm). Images were also corrected for attenuation and decay andnormalized for injected dose. Regions of interest were manuallyplaced over the different areas of the baboon brain with referenceto a baboon PET atlas (29), and time-activity curves were generated.

Brain kinetics ofthe radiotracerwere calculated by fitting all theregional radioactivity concentration values at the different timepoints to a triple exponential equation:

E(t) Ae@ + Be_at + Ce@t

where E is the brainradioactivity concentration and A, B and C arecoefficients for the initial rapid distribution (a), distribution!disposition (@3),and elimination (A) phases, respectively, with theconstraint E(0) = 0. The clearance t112was calculated as: t112=0.693/A. The time/activity data were fit using a nonlinear regres

sion program, MacCurveFit (Kevin Raner Software, Inc., Mt.Waverley, Victoria, Australia), run on a Macintosh personalcomputer.

0

FIGURE2. lime-activitycurvesfromthethalamus(I@HA@,hypothaiamus/midbrain(HYP/MD)andcerebellum(CB).Notethat inthe controlstudy (opensymbolsTHA0, HYP/MD0, CB L@)the radioactivityreachesa plateauaround 50 mm after radiotracer injection followed by a slow dissociation. Theadministrationof1mg/kgcy@alneat45mmaftertracerinjection(fullsymbolsTHAS, HVP/MDt CBA)markedlydecreasedthe18F-FPHbindinginallareas, showing specificity of the binding of 18F-FPH to nAChRS.

cytlslneI mg/kgscnCl/cc

800

600

400

200

0000 0 0

0 o oTHA

ODD 0

0 HYP/MB

.S

U.U

time(mm)

1738 THEJOURNALOFNUCLEARMEDICINE•Vol. 38 •No. 11 November 1997

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(Fig. 2). Elimination was relatively rapid from the cerebellum(clearance t112 = 3 hr), intermediate from the hypothalamus/midbrain (t112= 7 hr) and slow from the thalamus (t112= 16 hr).Radioactivity due to ‘8F-FPHat 130 mm postinjection washighest in the thalamus and hypothalamus/midbrain, intermediate in the neocortex and hippocampus and lowest in thecerebellum.

Subcutaneous injection of 1 mg/kg cytisine 45 mm after theinjection of the radiotracer reduced brain radioactivity at 130mm by 67%, 64%, 56% and 52% of control values in thethalamus, hypothalamus/midbrain, hippocampus and cerebellum, respectively (Fig. 3), indicating that the binding of‘8F-FPHto nAChRS is specific. There was no change in theradioactivity observed in the eyes after injection of cytisine(Fig. 3).

Binding of ‘8F-FPHat 130 mm was highly correlated withthe known densities ofnAChR measured in vitro by 3H-nicotine(r = 0.97), 3H-c@tisine (r = 0.97), 3H-epibatidine (r = 0.91 ) inrat brain and by H-nicotine in human brain (r = 0.81) (Fig. 4);in other words, high in the thalamus, intermediate in thehippocampus and low in cerebellum (25,30,31).

DISCUSSIONEpibatidine is reported to be the ligand with the highest

affinity for nAChRS in vitro (K1 —50 pM) (23). An analog ofepibatidine, FPH fumarate, competitively displaced 3H-epibatidine in in vitro binding studies with K@values of45 pM (32). Inthis study the kinetics and brain regional distribution of afluorinated analog of epibatidine, ‘8F-FPH,were successfullyexamined using PET. Although FPH produces toxicity in mice

In vivo In viva(nCIlcc) (nClIcc)

700 . 700

600 600

500 500

400 400

300 300

@ 2006 8 10 12 14 16 0 20 40 60 80 100

3H-nlcotlns(fmollmg tIssuS)@@ 3pg..@jytklea(f@wmgt1ssuS)@

In viva(naftc)

ThA

@A/@0 F@ 0.97

B mAy

@, LOB

PAR

0CB r=0.97

A

4

FIGURE4. Theinvivoregionaldistribution in the baboon is compared to theknown in vitro regional distribution ofnAChRsin the (A,B, C)ratand (D)humanbrains. NA = thalamus, LGB = lateralgenicullate body, STR = striatum,HIPP = hippocampus,FRO = frontalcortex,0CC = occipitalcortex,PAR=panetalcortexandCB = cerebellum.

20 30 40 50 60 70

3H-splbatldlns (fmollmg tlssus)25

10 203H-nlcotlns (pmoVg prot.In)31

IMAGING NICOTINIC RECEPTORS WITH PET . Villemagne et al. 1739

‘8F.IFPHPET Study130 mm post injection

Control@ S

@*@ 4a .

@@@@ @-@

Cytisine (1 mglkg DisplacementFIGURE a Black and white coded transforms of PET scans showing18F-FPH binding to the baboon brain at 130 mpi in the control study (upperrow)and afterdisplacementwith 1 mg/kgcytisine(lowerrow).Thereis adecreaseof binding in all brainareas,but there is no decreasein the activityintheeyes.

The in vivo regional binding in the baboon brain was comparedwith the known in vitro regional distribution of nAChRs labeledwith 3H-nicotine (30), 3H-cytisine and 3H-epibatidine (25) in therat brain and 3H-nicotine in human brain (31).

RESULTSRadioactivity was distributed heterogeneously in the brain.

Cortical, subcortical and cerebellar structures were well identifled (Fig. 1). Brain radioactivity reached a plateau approximately at 60 mm postinjection, and the binding was reversible

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(LD5O —40 nmollkg) (Scheffel, personal communication,1996), injection of the 5 mCi [185 MBq] dose of high specificactivity ‘8F-FPH(0.12 nmol/kg) did not cause a change ineither blood pressure or heart rate.

Although radioactivity was lowest in the cerebellum, there isno region of the brain completely devoid of nAChRs that islarge enough to be sampled by PET. There are species differences in the distribution of nAChRs in the mammalian brain.Binding of 3H-nicotine in the human brain is highest in thethalamus and striatum, intermediate in the hypothalamus andneocortex and lowest in the hippocampus and pons (31). Incontrast, 3H-nicotine binding is low in the monkey striatumcompared to the thalamus (33), while it is high in the neocortexofthe rat (18,30) and the mouse (34). A baboon was chosen forthis study because this is a Species close to humans and,therefore, the possibility ofsignificant species differences in thebiodistribution is reduced. In addition, the relatively large sizeof the baboon brain makes it suitable for PET imaging.

Fluorine-l8-FPH binding to nAChRs exhibits pharmacological specificity. Cytisine, a nicotine partial agonist, has highaffinity for the nicotine/ACh receptor subtype (1 7). Previousstudies using in vitro binding assay techniques, as well asfunctional assays, found that in the rodent brain both epibatidineand cytisine are bound to the nicotine/ACh subtype, mainlycomposed of a4f32 subunits (1). In vitro studies have shownthat (±)-epibatidine competitively displaced 3H-cytisine froma4f32 nAChRs subtypes in the rat brain in a concentrationdependent fashion consistent with a single-site competitivemodel with K1values of43 pM (35). After the administration ofcytisine, marked decreases in@ 8F-FPH binding were observedin regions of the brain known to contain high concentrations ofthe nicotine/ACh receptor subtype. Administration of cytisinehad no effect on ‘8F-FPHbinding in the region of the eyes,where the n-BgT receptor subtype abounds (36). Similar findings in the visual system were reported using 3H-epibatidine inrats (24,25). Our results provide further evidence that ‘8F-FPHbinds to nAChR subtypes other than the nicotine/ACh subtype.

The in vivo regional distribution of ‘8F-FPHis consistentwith the regional distribution of 3H-nicotine and 3H-cytisinebinding sites examined by in vitro methods in postmortemhuman, monkey and rat brains (25,30,31,33). Persistence ofFPH binding in the eyes afteradministrationof cytisine also isconsistent with the known distribution of the n-BgT receptorsubtype (36).

Collection of arterial plasma, and identification of metabolites in plasma, would be needed to further characterize thebinding of FPH in a quantitative fashion. Based on previousmouse data (32) and in our preliminary results, we think thatlonger scanning protocols would allow for equilibrium to beachieved. The advantage of studying receptors with a PETradiotracer labeled with a radioisotope such as ‘8F(T,,2 = 109mm) is that it allows for extended scanning after injection,which increases the contrast between regions of high- andlow-receptor density, permitting attainment of steady stateduring the scanning period, thus facilitating quantification ofthe binding potential, such as applied to other reversible bindingligands (37). However, this approach might not be feasiblebecause there is no region completely devoid of receptors thatcan be used as a reference region. Ifequilibrium is not achieved,and due to the toxicity ofepibatidine that precludes studies withlow specific activity as proposed by Huang et al. (38), fullkinetic compartmental analysis varying the available number ofbinding sites by a competing drug, such as cytisine, as proposedby Wong et al. (39,40), or a simplified approach using the

Gjedde-Patlak (41,42) linear transformation, could be applied.Further studies to address these issues are warranted.

CONCLUSIONThe results obtained in this study demonstrate the feasibility

ofnAChRs imaging in vivo with PET and suggest that ‘8F-FPHis potentially useful to study the physiologic role and thepathological states of nAChRs in the human brain.

ACKNOWLEDGMENTSThe authors thank Karen Edmons for her assistance with PET

data acquisition and Robert Smoot for technical assistance withcyclotron operation and radiochemistry. This work was supportedin part by U.S. Public Health Service grant # CA 32845, theDivision of Intramural Research, National Institute on Drug Abuse(NIDA), and funding for the NIDA Brain Imaging Facility from theCounterdrug Technology Assessment Center, Office of NationalDrug Control Policy.

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42. Patlak CS, Blasberg RG, Fenstermacher JD. Graphical evaluation of blood-to-braintransfer constants for multiple time uptake data. J Cereb Blood Flow Metabl983;3: 1—7.

malignancy.The delayed uptake ratio, retention ratio and retentionindex Significantly reflected tumor histology and clearly diStinguished between benign and malignant tumors with a statisticallyaignfficant ditference. There was no StatiStiCallysignificant differencein @°111Cluptakeor washoutamongthebraintumors.Technetium99m-DMSA is superior to 201T1C1in imaging quality, senSitivity tobraintumorsand specificityfor differentiatingbenigntumorsfrommalignant ones. These results could suggeSt the clinical utility of

@°@TC(@-DMSAin imaging primary and metastatic brain tumors anddifferentiating their histological malignancy grade noninvasively.

Key Words technetium-99m-DMSA thallium-201-chloride; histologic malignancy;brain tumor, retention index; SPECT

J NucI Med 1997;3&1741—1749

CTandMRIcandemonstratesmallerlesionsduetotheirfinespatial resolution. Furthermore, their contrast enhancement,mainly dependent upon disrupted blood brain barrier (BBB),has been used to localize the tumors, but prediction of histopathological diagnosis was very difficult. Thallium-20l-chloride, one of the most widely used radiopharmaceuticals, hasbeen reported to differentiate, to some extent, benign lesionsfrom malignant lesions of the lung (1 ), thyroid gland (2) andbrain tumors (3—7),depending upon the uptake ratio andprolonged washout phase of radiotracer from the tumor tissue(5—7).

Pentavalent 99mTc(V)DMSA was developed for a tumorimaging agent (8,9) and its accumulation has been reported in

This study was performedto compareimagingability betweenpentavalent @Tc-DMSAand 201T1C1in primary and metastaticbrain tumors and to evaluate the relationship between retentionand histologicmalignancy.Methods Patientswith a braintumorwere selected by MRI and/or CT. Dynarrnc,early and delayedstaticSPECT images of the brain were obtained immedlately, 30 mm and3 hrafterintravenousadministrationof approximately555 MBq

@Tc(V)-DMSAand 111 MBq 2o1@l respecThiely. Both studieswere performed on separate days within a week. Uptake ratios,retention ratio and retention index were calculated and comparedwith tumor histology and malignancygrade. Results One-hundredsix studies were performedon 100 patientsand 118 lesionsweredemonstrated:16glioblastomas,13anaplasticastrocytomas(Grade Ill), 19 astrocytomas(Grade II), 29 meningiomas,11schwannomas and 14 metastases.Approximately 93% and 88%,respectively,of primary and metastatic brain tumors were demonstrated by @Tc(V)-DMSAand @°111Cl.The early uptake ratioswereclosely related to the tumor vascularity, but had no StatiStiCallysignificantdifferenceinthetumorhistologyor histologicmalignancyon eitherradiopharmaceuticals.Thedelayeduptakeratio,retentionratio and retention index were higher in malignant tumors thanbenign ones on @°°@rC(V)-DMS@however,there was no StatiStiCallysignificant difference between benign and malignant tumorS on201flClConclusion:Technetium-99m@-DMSAwashoutfromthetumor was highly dependentupon its histologyand histologic

ReceivedSep. 10, 1996; revisionaccepted Feb.28, 1997.For correspondenceor reprints contact: Tsuneo Hirano,MD, 3-13-5 ShOWa-machi,

Maebashi,Gunma00371,Japan.

TECHNETIUM-99m(V)-DMSA AND T@LLlUM-201 IN BRAIN TUMOR IMAGING •Hirano et al. 1741

Technetium-99m(V)-DMSA and Thallium-20 1 inBrain Tumor Imaging: Correlation with Histologyand Malignant GradeTsuneo Hirano, Hidenori Otake, Ken Kazama, Kazuki Wakabayashi, Akira Zama, Takashi Shibasaki, Masaru Tamura andKeigo EndoDepartments ofNuclear Medicine and Neurosurgery, Gunma University, School ofMedicine, Maebashi, Gunma, Japan

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1997;38:1737-1741.J Nucl Med.   Henry N. Wagner, Jr. and Robert F. DannalsVictor L. Villemagne, Andrew Horti, Ursula Scheffel, Hayden T. Ravert, Paige Finley, David J. Clough, Edythe D. London,  Imaging Nicotinic Acetylcholine Receptors with Fluorine-18-FPH, an Epibatidine Analog

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