pride (RAC), which is a selective dopamine D2 receptorligand, increases in the striatum contralateral to the predominant symptoms of Parkinson's disease, compared withuptake in the opposite hemisphere (1—7).

In vitro studies indicate, however, that lack of dopaminemay itself produce an increase in [“C]RACuptake (8,9),possibly without a change in dopamine receptors. Young etal. (9) depleted dopamine stores with reserpine and showedan increase of more than 50% in striatal [3H]RAC binding inrats. Hall et al. (10) investigated the interaction of dopamineand dopamine D2 receptors labeled with [3H]RAC in ahuman postmortem study and found that endogenous dopamine interacted potently with dopamine D2 receptors in thecaudate nucleus. Increasing the dopamine concentrationdecreased the amount of [3HJRAC bound to the dopamineD2 receptors (10). Dewey et al. (11) investigated baboons ina PET study and reported a similar decrease in [“C]RACbinding after administration of d-amphetamine, which increases synaptic dopamine. In contrast to in vitro studies, thestudy of Dewey et al. also showed a significant decrease instriatal [“C]RACbinding after administration of tetrabenazine (a dopamine-depleting drug). As Dewey et al. point out,however, tetrabenazine has been shown not only to depletebiogenic amines, such as dopamine, but also to bind todopamine D2 receptors and thus compete with other dopaminergic antagonists such as [“C]RAC.

In the case of Parkinson's disease, in which the deficiencyof dopamine is a key phenomenon and in which [“C]RAChas been used in PET studies to show changes in thedopamine D2 receptor, this issue is crucial. If increaseduptake of [“C]RACto the contralateral putamen in PETstudies is merely an indication of dopamine deficiency inthat brain region, rather than a sign of altered receptordensity, re-evaluation of the studies already concluded isnecessary.

To show a possible change in kinetic properties of[“C]RAC,another dopamine D2 receptor ligand, which ispreferably stable in response to changes in endogenousdopamine, is needed. [3H}NMSP has a 10-fold higher

DopamineD2receptorfunctionwasassessedina PETstudywith2 dopamine D2 receptor PET ligands, [11C]raclopride(RAC) and[11C]N-methylspiperone (NMSP), in early Parkinson's disease.Methods:SevenpatientswithearlyParkinson'sdiseaseand5healthyvolunteerswere studied.EachunderwentPETbothwithreversible [11C]RACand with irreversible [11C]NMSP.Results:Upregulationof dopamineD2receptorsin the putamencontralateral to the predominantsymptoms of Parkinson'sdisease wasconfirmed using both [11C]RACand [11C]NMSP.Uptake of[11C]RACin the contralateralputamenwas 105%of uptakein theopposite putamen (P = 0.020). For [11C]NMSP,uptake in thecontralateral putamen was 105% of uptake in the ipsilateralputamen(P = 0.011).No significantdifferencesbetweenParkinson's disease patients and healthyvolunteerswere detected inany of the studied brain regions using either [11C]RACor[11C]NMSP. No significant differences between [11C]RAC and[11C]NMSPuptakewere detectedin the striatum,whereas in theextrastriatal regions, [11C]NMSPshowed significantly higheruptake than [11C]RACboth in healthyvolunteersand in Parkinson's disease patients. Conclusion: This study confirms anincrease in dopamineD2receptorsin the putamencontralateralto the predominant symptoms, compared with the ipsilateralputamen, in early Parkinson'sdisease.This increasewas seenboth with reversibleligand [11C]RACand with irreversibleligand[11C]NMSPand thus does not seem a consequenceof depletedendogenousdopamine.KeyWords:Parkinson'sdisease;dopamineD2receptor;raclopride; N-methylspiperone;PET

J NucIMed2000;41:65—70

he predominant pathology in Parkinson's disease isdegeneration of the nigrostriatal dopaminergic pathway,leading to a deficiency of endogenous dopamine in thestriatum. In addition to presynaptic changes in the nigrostriatal neurons, the striatal dopamine receptors alter. For instance, in early Parkinson's disease, uptake of [@C}raclo

ReceivedOct.25,1998;revisionacceptedJun.21, 1999.Forcorrespondenceor reprintscontact:Juha0. Rinne,MD,PhD,Depart

mentofNeurology,UniversityofTurku,FIN-20520Turku,Finland.

[‘1CIJRACAND[@CJNMSPmiP@auur@iSoN'SDISEASE•Kaasinenet al. 65

Upregulation of Putaminal Dopamine D2Receptors in Early Parkinson's Disease:A Comparative PET Study with [11C]Racloprideand [11C]N-MethylspiperoneValtteri Kaasinen, Hanna M. Ruottinen, Kjell NAgren, Perth Lehikoinen, Vesa Oikonen, and Juha 0. Rinne

Department ofNeurology, University ofTurku, Turku; and Radiopharmaceutical Chemistry Laboratory,Turku PET Centre, Turku, Finland

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

SubjectnAge

(y)Mean ±SDRangeSex F MSide

of predominantsymptomsDuration of disease

(mean ±SD) (mo)UPDRS*(mean ±SD)ALParkinson's

disease patients759.0 ±10.945—754 33414.7 ±5.014.1 ±6.9Healthyvolunteers557.2 ±9.552—7441———*Total

pointsscoredin motorpartof Unified Parkinson's DiseaseRatingScale.

affinity (Kd = 0.2 nmol/L versus K@ = 3.9 nmol/L) forputaminal dopamine D2 receptors than does [3H]RAC in thehuman brain (12). Depletion of brain dopamine has nosignificant effect on [3H]NMSP striatal binding (9).

Our study was designed primarily to determine whetherstriatal uptake of these 2 dopamine D2 receptor PET ligandsdiffers in vivo in patients with early Parkinson's disease.Finding no difference in striatal binding would indicate thatendogenous dopamine may not be the explanation for theincrease seen in [‘1C]RACbinding in early Parkinson'sdisease. For this purpose, the results obtained using bothradioligands were intraindividually compared.

MATERIALSAND METHODS

PatientsSeven patients with idiopathic, early Parkinson's disease and 5

healthy age-matched volunteers were studied. The patients hadpredominantly unilateral symptoms, and no patient had receivedantiparkinsonian medication. Four patients were receiving antihypertensive medication, and 1 patient was receiving anticholinergicmedication. The alcohol consumption of all subjects was occasional and moderate, and all subjects were nonsmokers. Theseverity ofParkinson's disease was assessed according to the motorpart of the Unified Parkinson's Disease Rating Scale (13). Table 1shows the main clinical characteristics of the patients. All gaveinformed consent. The study was approved by the ethical committee ofThrku University Central Hospital.

Radiochemistry

[“C]RACwas prepared as previously described (14), and thequality control of the product was performed using the method ofRinne et al. (15). [“CJNMSPwas prepared from [“Cimethyltriflate (16). A 1-pot procedure from [“C]carbondioxide was usedin the preparation of [“Cimethyliodide (17), which was convertedon-line to [UC]methyl triflate by passage through a silver triflategraphitized carbon column at l50°C—200°C(18,19). [“C]NMSPwas prepared by reaction of [“C]methyltriflate with the N-desmethyl precursor (spiperone; Sigma Chemical Company, St.Louis, MO), and the reaction solution was purified with a 7.8 X300 mm high-performance liquid chromatography column (iiBondapak C,,; Waters, Milford, MA) using a mixture of 10mmol/L phosphoric acid:acetonitrile, 65:35, at a flow rate of 6mLimin. The volume of the formulated (physiologic 0.1 molILphosphate buffer) [“C]NMSPsolution was determined by weightbefore and after sterile filtration. The concentration of [“C]NMSPin the formulated solution was determined by reversed-phase

high-performance liquid chromatography using a mixture of 10mmol/L phosphoric acid:acetonitrile, 65:35, at a flow rate of 2mLimin. Ultraviolet absorbance was measured at 250 nm. Samplesof [“CINMSPwere analyzed in triplicate, and concentrations weredetermined from calibration curves made by injection of 3 knownconcentrations of NMSP (Research Biochemicals International,Natick, MA) on the same day as the “Csynthesis, with an SD ofless than 2%.

PETEach subject was scanned with [“C]RACand [“C]NMSPin

random order on the same day using the same scanner and patientpositioning principles.

The [“C]NMSPscans were obtained with an ECAT 931/08-12PET scanner (CTI/Siemens, Knoxville, TN) with an averagein-plane spatial resolution of 6.5 mm (full width at half maximum)and an average axial resolution of 6.7 mm. [“C]NMSPscansconsisted of 27 consecutive frames (2 X 120 s, 6 X 60 s, 5 X 120s,and 14 X 300 s). The total duration of [“C]NMSPstudies was 90mm. The injected dose of [“C]NMSPwas 380 ±18.9 MBq(mean ±SD) (range, 360-417 MBq), with a specific radioactivityof 39.0 ±10.9 GBq/pmol (range, 22.6—59.3GBq4imol). Theweight of the injected dose of [“C]NMSPwas 4.31 ±1.31 jig(range, 2.42—6.73jig).

The [“C]RACscans were obtained using a method describedearlier (1,7). The injected dose of [“C]RACwas 200 ±15.2 MBq(range, 178—232MBq), with a specific radioactivity of 36.0 ±9.9GBq4unol (range, 17.6-49.1 GBq/pmol). The weight of theinjected dose of [“C]RACwas 2.09 ± 0.80 jig (range,1.34—4.16jig).

The region-of-interest analysis was performed by taking frontal,lateral temporal, occipital, and cerebellar cortices in each hemisphere as separate regions of interest. Moreover, regions of interestwere drawn on the caudate nucleus, putamen, amygdala, cingulategyms, and thalamus in each hemisphere. To exclude structurallesions and to create an anatomic reference, each individualunderwent brain MRI with a l.5-T superconducting unit (Magnetom; Siemens, Erlangen, Germany). PET and MRI planes wererealigned with a surface-fit computer program (20) so that theplanes corresponded in axial and transaxial positions. Regions ofinterest were delineated on the basis of the anatomic boundaries inthe horizontal MR images and transferred to the correspondingPET images. The distribution volume ratios, which are linearfunctions of receptor availability, were calculated using a graphicmethod described by Logan et al. (21) (Logan plot). Because of thecomparative nature of the study, the Logan plot was also used with[“CINMSPdata. [“C]NMSPresults calculated with a referencetissue model for irreversible ligands by Patlak and Blasberg (22)

TABLE1Clinical Characteristics of Parkinson's Disease Patients and Healthy Volunteers

66 THE Joui@i OF NUCLEARMEDICINE •Vol. 41 •No. 1 •January 2000

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

had a significant positive correlation with the results of the Loganplot. The linear stage of the Logan plot was achieved 15 mm afterinjection of [“C]RACand 20 mm after injection of [“C]NMSP(21).

StatisticsThe differences in distribution volume ratios between healthy

volunteers and Parkinson's disease patients were estimated by theMann-Whitney test. The distribution volume ratios in the regionsof interest between opposite hemispheres (contra- and ipsilateral tothe predominant symptoms) in Parkinson's disease patients werecalculated and tested against a null hypothesis of 0 (namely, nodifference between the hemispheres) using the paired t test.

RESULTS

Uptake of [“C]RACin the putamen contralateral to thesymptoms was, on average, 105% of uptake in the oppositeputamen (P 0.020). For [‘1C]NMSP,uptake in thecontralateral putamen was 105% of uptake in the ipsilateralputamen (P = 0.011) (Fig. 1; Table 2). No significantasymmetry of uptake was detected in any other brain region(e.g., in the contralateral caudate versus the ipsilateralcaudate) in Parkinson's disease patients or healthy volunteers.

Between the Parkinson's disease patients and the healthyvolunteers, no significant differences were detected in any ofthe brain regions studied, using either [“C]RAC or[“C}NMSP.No significant difference was detected betweenthe Parkinson's disease patients and the healthy volunteersin pooled average values of the 2 hemispheres or in thecomparison of contra- or ipsilateral putamen in Parkinson's disease patients versus the average value in healthyvolunteers.

In the striatum, no significant differences were seenbetween uptake of [“C]RACand uptake of [“C]NMSP.However, in the extrastriatal regions, uptake was significantly lower for [“C]RACthan for [“C]NMSPin both theParkinson's disease patients and the healthy volunteers(Table 3). In the extrastriatal regions, the difference in the

healthy volunteers was statistically significant in the frontalcortex, thalamus, occipital cortex, and temporal cortex. Inthe cingulate gyms, the difference did not reach statisticalsignificance. In the Parkinson's disease patients, all extrastriatal regions studied differed significantly between [“C]RACand [@C]NMSP, and the difference was also significant inthe ventral striatum.

DISCUSSION

Our results show that in early Parkinson's disease, theincrease in uptake to dopamine D2 receptors in the putamencontralateral to predominant symptoms, compared with theopposite putamen, is similar for [“C]NMSPand [“C]RAC.This finding suggests that the deficiency of endogenousdopamine does not explain the increased uptake of [“C]RACin PET studies of early Parkinson's disease (1—7).

In a PET study by Hagglund et al. (23) that used[11C]NMSP in 6 patients with different stages of Parkinson'sdisease, dopamine receptor densities of striatal structurestended to vary with the stage of disease. Uptake of[@C]NMSP was increased in patients whose disease was inHoelm and Yahr (24) stage 1 but was reduced in later stagesto a level lower than in healthy volunteers. Hagglund et al.did not, however, find any evidence supporting side-to-sidedifferences in the striatum, possibly because of the limitednumber of suitable patients in their study. Only 3 of the 6patients had unilateral symptoms and only 1 of those 3 wasnot treated with dopaminergic medication. In our patients,all of whom were not receiving medication and had strictlyunilateral symptoms indicating Hoehn and Yahr stage 1 or1.5, uptake of [“C]NMSPwas higher in the contralateralputamen than in the ipsilateral putamen.

The relative increase in [“C]RACuptake in early Parkinson's disease persists at least 6 mo after diagnosis (4). Thisupregulation disappears later, and when the disease isadvanced the [“C]RACuptake is reduced (25). This finding

FIGURE 1. Striatal [11C]RACand[11C]NMSPPET images of patientwithearlyParkinson's disease. Uptake of both radioligandsto contralateralputamenis asymmetric,comparedwith oppositeputamen. CL =side contralateral to predominant symptoms of Parkinson'sdisease.

CL CL

[“C]RACAND [‘1C]NMSPmr P@iuuNSoN'S DISEASE •Kaasinen et al. 67

II1CIRAC IIICJ1NMSP

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

Subject Putamen CaudatenucleusNo.

Sex Contralateral Ipsilateral ContralateralIpsilateral

TABLE2Individual and Mean DVRs in Putamen and Caudate Nucleus in Parkinson's Disease Patients and Healthy Volunteers

FMMFFFM

FFFMF

FMMFFFM

FFFMF

3.123.733.063.483.754.233.53

3.56 ±0.40*

2.993.483.003.463.483.863.41

3.38±0.30

3.173.253.472.873.713.613.79

3.41±0.33

2.593.212.572.813.123.182.92

2.91 ±0.27

2.823.242.643.143.233.412.42

2.97±0.36

2.612.823.012.322.922.602.78

2.72±0.23

3.623.033.013.583.76

3.40 ±0.35t

3.712.863.423.934.69

3.72±0.67t

[11C]NMSPParkinson's disease patients

234567

Mean±SDHealthyvolunteers

2345

Mean ±SD

[11C]RACParkinson'sdiseasepatients

234567

Mean ±SDHealthyvolunteers

2345

Mean ±SD

2.362.733.142.762.802.092.89

2.68±0.35

3.203.323.933.103.963.663.96

3.59±0.38t

3.203.023.743.423.48

3.37±0.28t

3.052.793.052.803.07

2.95 ±0.14t

*P = 0.011 compared with ipsilateral putamen.tMean ofleft andrighthemispherevalues.:$:P= 0.020comparedwithipsilateralputamen.

(32—34),and in a study comparing the results of 123Iiodobenzamide SPECT and [“C]RACPET (35), the frequency of side-to-side differences in striatal tracer bindingwas similar for SPECT and PET. Furthermore, quantitativeanalysis has shown that increased [@C]RAC binding inParkinson's disease is caused by a relative increase indopamine D2 receptor density rather than dopamine D2receptor affinity (7). In summary, the results of animal,postmortem, and PET studies have suggested that thenumber of dopamine D2 receptors in the denervated striatumincreases in Parkinson's disease. Our study confirms theincrease in dopamine D2 receptors in the putamen contralatera! to the predominant symptoms, compared with theopposite putamen.

Previously reported side-to-side differences were con

may be caused by a combination of the effect of dopaminergic medication and the disease process itself. However, in astudy by Antonini et al. (26), 3—4mo of oral therapy withlevodopa had only a minimal effect on striatal [“C]RACuptake in untreated Parkinson's disease patients. A similarincrease in receptor binding has been shown in experimentalmodels of Parkinson's disease. Unilateral destruction ofnigrostriatal projection with 6-hydroxydopamine in rats (27)or with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine inmonkeys (28,29) has increased striatal uptake of dopamineD2 receptor ligands. In humans exposed to l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine, a similar increase in dopamine D2 receptor binding has been reported (30,31). Inpostmortem brain studies of untreated patients with Parkinson's disease, a denervation upregulation has been found

68 Tmi Joui@i OF NUCLEARMEDICINE •Vol. 41 •No. 1 •January 2000

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

Parkinson'sdiseasepatientsHealthyvolunteers[11C]RAC

[11C]NMSP[11C]RAC[11C]NMSPBrainregion (mean±SD) (mean±SD) Duff(mean ±SD)(mean ±SD)DuffFrontal

cortex 1.12 ±0.07 1.40 ±0.08 20*1 .16 ±0.071 .45 ±0.0820*Temporalcortex 1.20 ±0.07 1.51 ±0.08 21 @1.23 ±0.071 .52 ±0.1319*Occipitalcortex 1.18 ±0.08 1.38 ±0.08 14*1.21 ±0.111.42 ±0.0915tThalamus

1.31 ±0.04 1.45 ±0.13 lOt1.35 ±0.061.56 ±0.1413tCingulategyrus 1.15 ±0.07 1.39 ±0.10 17*1.19 ±0.091.41 ±0.2016tCaudate

nucleus 2.71 ±0.26 3.04 ±0.29 11@2.95 ±0.143.40 ±0.3513@Putamen3.48±0.38 3.52±0.37 It3.37 ±0.283.72 ±0.679@Ventral

striatum 2.09±0.38 2.71±0.34 23t1 .93 ±0.232.32 ±0.9817t*P<

0.05.tP<0.01.SNot

statisticallysignificant.Diff= percentage difference between DVRs of[11C]RACand[11C]NMSP.In

caudate-putamen, no significant differenceexists between [11C]RACand [11C]NMSP.Valuesarepooled from both hemispheres.

TABLE3Comparison ofthe DVRs Obtained with [11C]RACand [11C]NMSPin Parkinson's Disease Patients and Healthy Volunteers

finned in this study using both the [“C]RACand the[‘tC]NMSPradioligands. The Parkinson's disease patientsdid not, however, show the overall increased [“C]RACor[“C]NMSPbinding in the striatum, compared with agematched healthy volunteers, that some studies have found(7,23,25,26). This inconsistency appears to be caused by therelatively small number of subjects in our study andinterindividual variation. Furthermore, dopamine D2 receptor binding characteristics generally do not seem to reliablyseparate Parkinson's disease patients from healthy volunteers (7,25).

In this study, uptake of [@C]NMSP was significantlyhigher than uptake of [“C]RACin extrastriatal regions.Although not as selective a dopamine D2 receptor ligand as[“C}RAC,[“C}NMSPis also a serotonin S2receptor ligand(36). Because of the different binding profiles, the difference

in cortical uptake of [@C]RAC and [“CJNMSPdoes notreflect changes in dopamine D2 receptors. Binding of[“C]NMSPto serotonin receptors is relatively higher inextrastriatal regions, where dopamine D2 receptor density islow, than in the striatum and may cause 10%—20%higher[“C]NMSPradioactivity (Table 3). However, no differencesin either [“C]RACor [‘1C]NMSPextrastriatal uptake werefound between healthy volunteers and Parkinson's diseasepatients. To detect differences in low-density extrastriataldopamine D2 receptors between diseased and healthy mdividuals, ligands with both high selectivity and high (picomoles per liter) affinity have to be used.

CONCLUSION

This study confirms an increase in dopamine D2 receptorsin the putamen contralateral to the predominant symptoms,compared with the ipsilateral putamen, in early Parkinson'sdisease. This increase does not seem to result from reducedendogenous dopamine concentrations.

[“CJRACAND [@C]NMSP m@P@iurs@SoN'SDISEASE •Kaasinen et al. 69

ACKNOWLEDGMENTS

This study was supported by the Päivikki and SakariSohlberg Foundation and the Turku University Foundation.The assistance of the staff of the Turku PET Centre isgratefully acknowledged.

REFERENCES1. Rinne UK, LaihinenA, Rinne JO, NâgrenK, Bergman J, Ruotsalainen U. Positron

emission tomography (PET) demonstrates dopamine D-2 receptor supersensitivity in the striatum of patients with early Parkinson's disease. Mov Disord.1990:5:55—59.

2. Rinne JO, Laihinen A, NAgren K, et al. PET demonstrates different behaviour ofstriatal dopamine D-l and D-2 receptors in early Parkinson's disease. I NeurosdiRes. 1990:27:494-499.

3. Leenders K!, AntoniniA, Gut F, Scherer U, Hess K. Striatal dopamine D2receptordensity in Parkinson's disease measured with PET using [“Cjraclopride [abstract]. Neurology. 1991;41(suppl l):211.

4. Rinne JO, Laihinen A, Rinne UK, NAgren K, Bergman J, Ruotsalainen U. PETstudy on striatal dopamine D2 receptor changes during the progression of earlyParkinson's disease. Mov Disord@1993:8:134—138.

5. Sawle GV, Playford ED, Brooks DJ, Quinn N, Frackowiak RSJ. Asymmetricalpre-synaptic and post-synaptic changes in the striatal dopamine projections indopa naïveparkinsonism. Brain. 1993;116:853—867.

6. Snow BJ, Buckley K, Bailey D, et al. Dopamine D2 receptor density is inverselycorrelated with dopaminergic innervation in untreated Parkinson's disease [abstract]. Neurology. 1993;43(suppl):269.

7. Rinne JO, Laihinen A, Ruottinen H, et al. Increased density of dopamine D2receptors in the putamen, but not in the caudate nucleus in early Parkinson'sdisease: a PET study with [“C]raclopride.JNeurol Sd. 1995:132:156—161.

8. Seeman P, Guan HC, Niznik HB. Endogenous dopamine lowers the dopamine D2receptor density as measured by [3H]raclopride: implications for positronemission tomography ofthe human brain. Synapse. 1989:3:96-97.

9. YoungLT,WongDF,Goldman5, et al. Effectsof endogenousdopamineonkinetics of [3H]N-methylspiperone and [‘H@]racloptidebinding in the rat brain.Synapse.1991:9:188—194.

10. Hall H, Farde L, Sedvall 0. Human dopamine receptor subtypes: in vitro bindinganalysis using 3H-SCH 23390 and 3H-raclopride. I Neural Transm. 1988:73:7—21.

11. Dewey SL, Smith OS, LoganJ, Brodie ID, FowlerJS, Wo1fAP. Striatal binding ofthe PET ligand @C-racloprideis altered by drugs that modify synaptic dopaminelevels. Synapse. 1993:13:350—356.

12. Hall H, Wedel I, HaIIdin C, Kopp J, Farde L Comparison of the in vitro receptorbinding properties ofN-[3Hjmethylspiperone and @HIrac1oprideto rat and humanbrain membranes. JNeurochem. 1990:55:2048—2057.

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

13. Fahn 5, Elton RL, and the UPDRS Development Committee. Unified Parkinson'sDisease Rating Scale. In: Fate 5, Marsden CD, Caine DB, Goldstein M, eds.Recent Developments in Parkinson ‘aDisease. Florham Park, NJ: MacMillanHealthcareInformation:1987:153—163.

14. Haildin C, Farde L, Hogberg T, et al. A comparative PET-study of five carbon-Ilor fiuorine-18 labelled salicylamides: preparation and in vitro dopamine D-2receptor binding. Nud Med Biol. 1991 ;18:871—881.

15. Rinne JO, Hietala J, Ruotsalainen U, et al. Decrease in human striatal dopamineD2 receptor density with age: a PET study with “C-raclopride.I Cereb BloodFlow Metab. 1993:13:310—314.

16. NAgren K, Halidin C. Methylation of amide and thiol functions with [@C]methyltriflate, as exemplified by [“C]NMSP,[@‘C]flumazeniland [“C]methionine. ILabelled Cpd Radiopharm. 1998:41:831—841.

17. LAngstrOmB, Antoni 0, Gullberg P. et al. The synthesis of 1-―C-labelledethyl,propyl. butyl and isobutyl iodides and examples of alkylation reactions. AppIRadio:1501.1986:37:1141—1145.

18. Jewett DM. A simple synthesis of [“C]methylinflate. AppI Radiat Isot.1992:43:1383-1385.

19. NAgren K, MUller L, Halldin C, Swahn C-G, Lehikoinen P. Improved synthesis ofsome commonly used PET radioligands by the use of [“C]methylinflate. NuclMedBiol. 1995:22:235—239.

20.Pellizari,CA,ChenGTY,SpelbringDR.WeichselbaumRR,ChenCT.Accuratethree-dimensional registration of CI', PET, and/or MR images of the brain. ICompAssist Tonwgr@1989:13:20—26

21. Logan J, Fowler iS, Volkow ND, wang GJ, Ding YS, Alexoff DL. Distributionvolume ratios without blood sampling from graphical analysis of PET data. ICereb Blood Flow Metab. 1996:16:834—840.

22. Patlak CS, Blasberg RG. Graphical evaluation ofblood-to-brain transfer constantsfrom multiple time uptake data: generalizations. I Cereb Blood Flow Metab.1985:5:584—590

23. Hagglund J, Aquilonius S-M, EckernäsS-A, et al. Dopamine receptor propertiesin Parkinson's disease and Huntington's chorea evaluated by positron emissiontomography using “C-N-methyl-spiperone. Acta NeurolSdamL 1987:75:87—94.

24. Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology. 1967;l7:427—442.

25. Brooks Di, Ibanez V. Sawle GV, et al. Striatal D2 receptor status in patients withParkinson's disease, striatonigral degeneration and progressive supranuclear

palsy, measured with “C-racloprideand positron emission tomography. Ann

Neurol. 1992:31:184—192.

26. Antonini A, Schwarz J, Oertel WH, Beer HF, Madeja UD, Leenders KL.

[“C]racloprideand positron emission tomography in previously untreated pa

tients with Parkinson's disease: influence ofL-dopaand lisuridetherapy on striatal

dopamine D2-receptors. Neurology. 1994:44:1325—1329.27. Creese I, Burt DR. Snyder SH. Dopamine receptor binding enhancement

accompanieslesion-inducedbehavioural supersensitivity. Science. 1977:197:596—598.

28. Leenders IU, Aquilonius SM, Bergstrom K, et al. Unilateral MFI'P lesion in arhesus monkey: effects on the striatal dopaminergic system measured in vivo with

PETusingvariousnovel tracers.BrainRes. 1988:445:61-67.29. TedrOffJ. Parkinson ‘aDisease: Pathophysiology and PET[dissertationl. Uppsala,

Sweden: Uppsala Universitet; 1990.

30. Caine DB, Langston JW, Martin WR, et at. Positron emission tomography afterMPTP: observations relating to the cause of Parkinson's disease. Nature.

1985:317:246—248.

31. Perlmutter JS, Kilbourn MR. Raichle ME, Welch MJ. MFFP-induced upregulation of in vivo dopaminergic radioligand-receptor binding in humans.Neurology 1987;37: 1575—1579.

32. Guttman M, Seeman P. L-dopa reverses the elevated density of D2 dopamine

receptors in Parkinson's diseased striatum. JNeural Transm. 1985;64:93—103.

33. Lee T, Seeman P, Rajput A, Fancy U. Hornykiewicz 0. Receptor basis fordopaminergic supersensitivity in Parkinson's disease. Nature. 1978:273:59—61.

34. Rinne UK, Koskinen V. Ldnnberg P. Dopamine receptors in the parkinsonianbrain.JNeuralTransm.1981:51:97—106.

35. Schwarz J, Antonini A, Tatsch K, Kirsch C-M, Oertel WH, Leenders KL.Comparison of °@I-IBZMSPECT and “C-raclopridePET findings in patientswith parkinsonism. NuclMed Commun@1994:15:806-813.

36. Lyon RA, Titeler M, Frost JJ, et a!. 3H-3-N-methylspiperone labels D2 dopaminereceptors in basal ganglia and S2 serotonin receptors in cerebral cortex. INeumsdi. 1986:6:2941—2949.

70 THEJOURNALOFNUCLEARMEDICINE•Vol. 41 •No. 1 •January 2000

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from

2000;41:65-70.J Nucl Med.   Valtteri Kaasinen, Hanna M. Ruottinen, Kjell Någren, Pertti Lehikoinen, Vesa Oikonen and Juha O. Rinne 

-MethylspiperoneNC]11C]Raclopride and [11Comparative PET Study with [ Receptors in Early Parkinson's Disease: A2Upregulation of Putaminal Dopamine D

http://jnm.snmjournals.org/content/41/1/65This article and updated information are available at:

  http://jnm.snmjournals.org/site/subscriptions/online.xhtml

Information about subscriptions to JNM can be found at:  

http://jnm.snmjournals.org/site/misc/permission.xhtmlInformation about reproducing figures, tables, or other portions of this article can be found online at:

(Print ISSN: 0161-5505, Online ISSN: 2159-662X)1850 Samuel Morse Drive, Reston, VA 20190.SNMMI | Society of Nuclear Medicine and Molecular Imaging

is published monthly.The Journal of Nuclear Medicine

© Copyright 2000 SNMMI; all rights reserved.

by VCU Libraries-Serials on March 10, 2015. For personal use only. jnm.snmjournals.org Downloaded from