P. B. Zanzonico, R. E. Bigler, and B. Schmall- Neuroleptic Binding Sites: Specific Labeling in Mice with [^18]Haloperidol, A Potential Tracer for Positron Emission Tomography

8/3/2019 P. B. Zanzonico, R. E. Bigler, and B. Schmall- Neuroleptic Binding Sites: Specific Labeling in Mice with [^18]Haloperi

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BAS IC SCIENCES

RADIOCHEM ISTRY AND RADIO PHARMACEUTICALS

Neu ro le ptic B in din g S ite s: Specific L abelin g in M ice w ith [1 8]Halo pe rid ol, APotentia l T race r fo r Pos itron Em ission Tomography

P . B . Z an zo nico , R . E . B ig le r, a nd B . S chma llMemoria l S lo an -K ette rin g C an ce r C en te r, N ew Y ork , N ew Y ork

Halo pe rid ol la be le d w ith flu orin e-1 8 (T i/a = 1 10 m in , p os itro n emis sio n 9 7% ),p repared y ie ld ing .04 Ci/m l llimo le by the Ba lz -Schi emann reac tion , was evalua tedin a murine model as a poten tia l r ad io tr ace r fo r noninvas ive de te rm ina tion , by posit ron-emission tomography, of regional concent rations of brain dopamine receptorsin patients. As the haloperldol dose In m ice was increased from 0.01 to 1000f ig /k g , t he r ela ti ve c onc e nt ra tion o f [ 18 F ]ha loper ido l (/ Cipe r g s pec m e n /tC ierg of body m ass), at one hour after injection decreased from 30 to 1.0 in the strl-a tum and fr om 8 .0 to 1 .0 in the cerebe llum . The s tr ia ta ! radioac tiv ity , p lo tted as r ela tiv e c on centra tio n a ga in st lo g o f d os e, d ec re as ed s igmoid ally , p re sumably refle cting competition between labe led and unlabe led halope ridol fo r a s ingle c la sso f accessible b ind ing s it es . Because the cerebell um is rela tive ly de fic ien t in dopam in e re ce pto rs , th e obs erv ed d ec re as e in c ere be lla r ra dio ac tiv ity may re fle ct asaturab le component o f ha loper ido l tr ansport in to bra in . The h igh bra in concentrati ons and the unexpec ted ly h igh s tr i tum-to-ce rebellumconcentrati on rat ios (>4a t ha loper ido l doses


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BASIC SC IENCESR AD IO CH EM IS TR Y A ND R AD IO PH ARMA CE UT IC AL S

carbon-1 1 or fluorine-18, the th eoretical m axim umspeci fi c ac ti vi ti es a re 9 .2 X IO6and 1 .7 X IO6Ci/mmole,respectively.Haloperido l and sp iroperido lpo ten t neuro lep tics ofth e b uty ro ph en on e se rie s, w id ely u se d in th e m an ag ement o f s ch iz op hre nia h av e b een s hown to b in d s pec ific ally , re ve rs ib ly , a nd w ith h ig h a ffin ity to s yn ap ticmembrane p re pa ra tio ns i n v itro (2 2). D emons tra tio n inv iv o o f s pe ci fic s piro pe rid ol b in din g s ite s h as b een a ccompl is hed u sing speci fi ca ll y t ri ti at ed spi roper idol s o fh igh speci fi c act iv it y, n ame ly l -pheny l- [3 -3H ]spi rop -eridol (sp . ac. 8-15 C i/mm ole) (27 -30) a nd 1-p henyl-[4 -3H]sp iro pe rid ol (3 0 C i/mmole ) (3 1,3 2), a nd a lso/>-[77Br ]bromosp i roper ido l (5-10 Ci /mmole) (33 ,34).R ad io ch em ic al s ta bility o f th e tritia te d li ga nd s in v iv oh as b een d emons tra te d b y th in -la ye r c hromato gra ph y(TLC) ( 27 ,29 ,31) . I n t he case o f l -pheny l- [3H ]spi rop-e rid ol, th e s tria tum -to -c ere be llum radio ac tiv ity c oncent ra ti on r at io a t 1 h r a ft er i nj ec ti on dec reas ed f rom 8 .8to 1 .0 a s th e sp iro pe rid ol d ose w as in cre as ed from 4 4 to2 00 0 Mg /k g (2 7,2 9). B ec au se d op am in e re ce pto rs a rea bu nd an t in th e s tria tum and re la tiv ely d efic ie nt in th ecer ebel lum (22 ), t hi s d ec reas e in the s tr ia tum-to- ce reb ellum ra tio p re sumab ly re fle cts s at ura tio n o f s tria ta ld op am in e re ce pto rs a nd th e e nsu in g d os e-d ep en de ntdec reas e in the p ropo rt ion o f speci fi ca ll y bound spi roperidol in brain. In contrast, dem onstration in vivo ofs pe cific h alo pe rid ol b in din g s ite s u sin g t ritia te d h alo -p erid ol h as n ot y et b een a ccomp lis hed. T he s pe cific a ct iv it ie s o f r andomly l abel ed t ri ti at ed ha lope ri do l ( 0.042C i/mmole ) a nd o f 4 '-flu oro bu ty ro ph en on e-[2 '-3H]-haloperidol (0.1 C i/m mole), though adequate forpharmacok ine ti c s tudi es ( 35 -40 ), a re appar en tl y t oo lowfo r th e d isc rim in atio n o f s pe cific ally lo ca liz ed fromnonspec if ic al ly l oca li zed ha lope ri do l i n b ra in ( 37 ,40) .T ho ug h o f a de qu ate ly h ig h sp ec ific a ctiv ity , th e u ne xp ec te d a bse nc e o f se le ctiv e stria ta l lo ca liz atio n o f 4 -(4-ch lo ropheny l) -[3-3H]-haloper ido l (8-18 Ci /mmole)at a haloperidol dose of only 5 M g/kg (30) suggests,p e rhap s, t ha t i t may unde rgo spon taneou s de- tr it ia ti onin v ivo .W e have prepared [l8F]haloperidol by the Balz-S chiem an n reac tion and hav e evaluated it in a m urinemod el a s a ra dio lig an d fo r th e sp ec ific la be lin g in v iv oo f n eu ro le ptic b in din g site s. B ec au se o f th e te ch nic alconstraints imposed by a short-l ived, cyclotron-producedr ad ionucl id e such as f luor in e- 18 , we have concur rent lyevaluated [G -3 H]haloperidol as a convenien t m odelr ad io li gand f or t he det erm inat ion o f t he do se -dependen tre gional conc entrations o f haloperidol in brain. [G -3H]Ha loper idol i s commerc ia ll y ava il ab le and has beenu sed in re cepto r b in di ng a ss ay s in v itro (4 1,4 2). [I8 F]-H alo pe rid ol p re pa re d b y th e Balz -S ch iemann re ac tio nin clu de s c arrie r b ec au se flu orin e-1 8 is in tro du ce d b yisotopie exchange w ith stable fluorine in the corresp on din g te tra flu oro bo ra te d ia zo nium sa lt (4 3-4 4).

(S chmall B , T ilb ury RS , N is se lb aum , J S, u np ub lis heddata). A lthough the resulting specific activity 400mCi/mmole appears to be som ew hat low for re ceptors tu die s in v iv o, s uch s tu die s a re fe as ib le in th e " pa rtia l-b od y countin g fa cili ty " a h ig h-s en siti vity , low-b ackground radiat ion coun t ing fac il ity designed and ins ta lledin o ur c en te r's b io ph ys ic s la bo ra to ry (4 5) .

M ATERIALS AND M ETHODSChemica ls .A l l commercia llyobta ined chemica ls andsolvent swere o f r eagen t g rade and were u sed as suppl ied .H alop eridol in cry stalline form w as a gift.* [G -3H ]-Ha loper idol ( 14 C i /mmo le ) was obt ai ned commer ci al ly .T he ra dio ch em ic al p urity (9 7%) was v erifie d b y TLC onsilica gel* jn chloroform /m ethanol/amm onium h ydrox ide (98:2:1) .An ima ls .A l l e xp er iment s u sed ma le and f ema le B6mic e, ma in ta in ed o n a 1 2-h r lig ht-d ar k cyc le , w ith fre ea cc ess to fo od a nd w ate r a nd h ou se d 8 -1 0 to a c ag e. T he

m ic e w ere a pp ro xim ate ly s ix mon th s o ld a nd w eig he d20-25 g each.Preparationand analysis of "de-fluorinatedhaloperido l" . Th is compound , 4 -[4- (4 -ch lorophenyl )-4-hy -d roxypipe ri di no ] butyr ophenone , appea rs t o be a l ig andb in din g to d op am in e re cepto rs (4 6), a nd was th ere fo rep re pa re d a s a n a na ly tic al sta nd ard fo r h ig h-p re ssu reliq uid chrom atography. It w as synthesize d by the N -alkylat ion of 4-(4-chlorophenyl) -4-hydroxypiper idinew ith -y -c hlo ro bu ty ro ph en on e, a nd wa s p urifi ed b y re -crys ta ll iza tion f rom 95% ethanol (mp:125-128C; Ref.4 6: 1 28 -1 30C ). T hin -la yer ch roma to gra ph y o f th ep ro du ct y ie ld ed a sin gle sp ot (R f = 0 .7 5). T he id en tityo f th e p ro du ct w as v erifie d b y chem ic al io niz atio n ma ssspectrometry.Preparationandanalysisof [18F]haloperidol.Th is wasp re pa re d from th e corre sp on din g te tra flu oro bo ra te d ia zo nium sa lt (c hemic al y ie ld 2 0-3 0% , ra dio ch em ic aly ie ld 0 .5 -1 .0%) b y th e Ba lz -S ch iemann re ac tio n u sin gaqueou s [ 18F]f luor id e, a s developed by Kook e t a l. ( 43 )a nd adapte d b y Schmal l a nd B ig le r (4 4). [I8 F]F lu orid ew a s p ro du ced in o ur c ompac t medic al c yc lo tro n v ia th en uc le ar re ac tio n 1 6O (3 //e ,p )1 8F b y th e irra dia tio n o fw ate r w ith 2 2-M eV h elium-3 io ns (4 7,4 8). C hemic ala nd ra dio ch em ic al p urity w as g re ate r th at 9 5% , a s d etermined by reverse i so tope d ilut ion analys is , thin -layerchr oma tog raphy, and h igh- pr es su re l iquid chr oma togra ph y. R ev ers e iso to pe d ilu tio n a na ly sis w as a cc omp lished by ch rom atogra phing an adm ixtu re of [I8F ]-h a lope ri do l and a l ar ge exces s o f unl abe led haloper ido lo n n eu tra l a lum in a (B ro ckman a ct iv ity 1 , 8 0-2 00 me sh )a nd com paring its spec ific a ctivity before and afterchr oma tog raphy. Analys is o f t he p roduc t by thin- laye rchromatography on silica gel in chloroform/m eth an ol/ammon ium h yd ro xid e (9 8:2 :1 ) a nd in c hlor of orm/e thy l ace ta te /f orm ic acid ( 5:4:1 ) y ie ld ed s ingl e

V olum e 24, N um ber 5 40 9


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ZA NZO NICO , B IG LER , A ND SC HMALLradioactive spots (R f = 0.75 and 0.3 6, resp ectively)id en tic al to th os e o f h alo pe rid ol. H ig h-p re ss ure liq uidchromato gra ph y o f th e p ro du ct w as c arrie d o ut u sin g anana ly tic al re ve rs e-p ha se (PAX 5 -1 025 ODS-3 ) c olumnand a solvent system of 0.1 mM ammonium acetate/m ethanol (65:3 5). M ass and rad ioactivity w ere m easured sim ultaneously using a refractom eter and aN al(T l) w ell counter w ith lo garithm ica lly scale d rad ia tio n me te r, re sp ec ti ve ly , i nte rfa ced to a d ua l-tra cestrip-chart record er. T he retentio n tim e for defluo-rinated haloperid ol w as 11 m in (k ' = l .2) and for haloperido l 12 m in (k' = 1.4). H igh-p ressure liq uid chrom ato gra ph y y ie ld ed a sin gle m ass p ea k a nd a sin gle rad io ac tiv e p ea k, c o-e lu tin g w ith p re cise ly th e same retentio n tim e as haloperidol. T he re w as n o detectabledef luor in at ed haloper idol i n t he [ 18F]haloper idol p repa ra ti on . T he s pe cific a ctiv ity o f [1 8F ]h alo pe ri do l, d ete rm in ed u sin g u ltra -v io le t s pe ctro ph otome try a nd ac ali bra te d Nal(T l) w ell c ou nte r, w as 0 .2 -0 .4 C i/mmolea t th e tim e o f in je ctio n.Injectionanddissectionprocedure.Mice were injectedunder light ether anesthesia w ith either [G -3H ]- or[ 18F]halope ri do l i n 0 .1 ml acidi fi ed , e th anol ic i so ton ics al in e v ia t he r et ro -o rb it al v enous p lexu s. The do ses were1 .0 , 1 0, 2 5, 1 00 , a n d 1 000/i g/k g fo r [G -3H] h a lo pe rid oland 0.010, 0.10, 1.0, 10, 25, 100, and 1000 M g/kg for[18F]haloperido l, ad jus ted before injec tion as necessaryb y th e adm ix tu re o f a n app ro pria te amount o f u nl ab ele dh alo pe rid ol w ith th e ra dio ag en t. T he re w ere fo ur m ic eper dosage group. Each mouse was killed at 1 hr byc erv ic al d is lo ca tio n and immed ia te ly d ec ap it ate d. T heen ti re b ra in was r emoved and p laced on an i ce -coldme ta ls urfa ce . T he s tria tum a nd th e c ere be llum w ere e xc ise da ccord in g to th e me th od o f G low in sk i a nd Iv ers en (4 9).Each tissue specim en was placed on a tared piece ofw eig hin g p ap er, th e p ap er a nd sp ec im en w eig he d, a ndthe wet m ass of the specim en determ ined by difference.Count ing o f tri tium in t is sue specimens . Each t is suespecim en w as placed in a 20-m l glass counting vial.E no ugh tis su e s olu biliz er (ty pic al ly 0 .5 m l) w as add edto each vial to im merse the tissue com pletely. Thespecim ens w ere incubated for 48 hr at 50 C .A fterc oo lin g, 1 5 m l o f sc in tilla tio n c oc kta il1 w ere a dd ed toe ach v ia l a nd th e ra dio ac tiv ity c ou nte d in an automat icb eta counter using a p reset "tritium " energy w indow .The cou nti ng e ffic ie ncy fo r tritium was 5 8% . Know in gth e ma ss and th e a ctiv ity p er u nit ma ss o f th e ra dio ac tiv eso lu tio n in je cte d in to e ac h mou se , th e in je cte d d ose o factivity w as determ ined. A fter correcting for background, the am ount of radioactivity in each tissues pe cimen wa s exp re ss ed a s re la tiv e con centra tio n ( uC ifound per g specim en/M Ci injected per g body m ass(50).Countingof fluorine-18 in tissue specimens. Fortissues pe cimens from mic e in je cte d w ith h alo pe rid ol d os es o f

1 M g/kg or less, each specim en w as placed in a sm allp oly eth yle ne tu be and th e ra dio ac tiv ity c ou nte d b y ann ih ila tio n coin cid en ce d ete ctio n. T his u tiliz ed th e p art ia l -body-count ing fac il ity, a r ad ia tion coun ter us ing twoh eavily s hi eld ed Nal(T l) c ry sta ls 2 3-cm in d iamete r b y13 cm thi ck . When ope ra ted in coinc id ence ( co in c id encere so lv in g time : 1 00 n se c) a nd w ith a c ry sta l s ep ara ti ono f 4 cm , t he b ackg ro un d countin g ra te is 0 .7 -0 .8 cpm andth e o ve ra ll c ou nt in g e ffic ie ncy fo r 0 .5 11 -MeV ann ih ila tio n p ho to ns i s ~2 0% . For tis su e s pe cimens fr om mic ew ith haloperidol doses of 10 M g/kg or greater, eachsp ec im en w as p la ce d in a 2 0-m l g la ss c ou ntin g v ia l a ndthe radioactivity counted in an automatic gamm acounte r w ith an ene rg y w in dow spann in g 4 50 -5 70 k eV .A fter correcting for backgrou nd and for decay (to thetim e o f in je ctio n), th e amo un t o f ra dio ac tiv ity in e ac hspecimen was exp re ss ed as r el at iv e concen tr at ion .Analys is o f the chemica l form of radioact iv ity in v ivo .T he striata and the cereb ella of severa l m ice injec tedw ith [G-3H]h alo pe rid ol o r w ith [1 8F ]h alo pe rid ol w e recomb ined in ch lo ro fo rm and homogen ized manua ll y w i tha g la ss h omogeni ze r. E ach o f th e re su ltin g s us pens io nsw as filte re d a nd a n a liq uo t o f e ac h o f th e re sp ec tiv e filtra te s a dm ix ed w ith h alo pe rid ol. E ac h o f th e re su ltin gs olu tio ns w as ana ly zed b y TLC.

RESULTSStr ia ta ! andcerebe ll ar H-3 concentrat ionsa s a functio n o f h alo pe rid ol d ose . F ig ur e 1 sh ow s th e r ela tiv econcen tr at ions o f t ri ti um in the s tr ia tum and cer ebe ll umof m ice, as a function of dose, 1 hr after the adm inistra tio n o f [G -3H] h alo pe rid ol. A s th e lo g d ose o f h alop erid ol is in cre as ed from 1 .0 to 1 000Mg /k g, th e re la tiv econcentrations of tritium in the striatum and in thec ere be llum remain con sta nt a t a v alu e o f a pp ro xima te ly2.0.S triata! an d cereb ellar F -18 con cen tr ation s as afunct ionof ha loperidoldose. F igure 2 shows the rela t ivec on ce ntra tio ns o f F -1 8 in th e stria tum a nd c ere be llumo f m ic e a s a fu nc tio n o f d os e 1 h r a fte r th e adm in is tra ti onof [18 F]haloperidol. A s the log dose of haloperid ol isincreased from 0.01 to 1000 M g/kg, the relative concentrations of fluorine-18 in the striatum and in thec ere be llum d ec re ase in a sigmo id al fa sh io n. T he d ose -

depend ent fall-o ff in the striatum is m uch m ore rapidthan that in the cerebel lum. The s tr ia tum- to -cerebel lumfluorine-18 concentration ratio, show n in Fig. 3 as af unct ion o f l og dose o f ha lope ri do l, l ik ewi se dec reas es i ns igmoidal f ash ion .Chemi ca l f orm o f rad io ac tiv it y in v iv o. Th in -la ye rchrom atography of tritium in m ouse brain yielded achromato gram on whi ch th e ra dio ac tiv ity w a s d iffu se lyd is trib ute d. T he a bse nc e o f a n ota ble ra dio ac tiv e sp otc o-m ig ra tin g w ith h alo pe rid ol su gg ests th at [G -3H]-h alo pe rid ol h as u nd er go ne s ub sta ntia l d e-tritia tio n in41 0 THE JOURNAL OF NUCLEAR MEDICINE


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BASIC SC IENCESRADIOCHEM IS TRY AND RAD1OPHARMACEUTICALS

STRIATUM

CEREBELLUMI J_ J_ J1000.0 10 100HALOPERIDOLDOSE(/ /g/kg)FK .1 . R ela tiv e c on ce nt ra tio ns o f [G -3 H] ha lo pe rid ol in s tr ia tum

and cerebellum of m ice at 1 hr after injection, as a function of adm in is te re d d ose o f h alo pe rid ol . E rr or b ar s r ep re se nt s ta nd ar d e rr oro f th e m ea n.vivo. In contrast, T LC of F -18 in m ouse b rain yield ed achrom atogram having a single radioactive spot, co-m igrating p recisely w ith haloperidol (R f = 0.75) andaccountin g for at least 80% of the rad ioactivity on th ech rom atog ram. B eca use o nly a sin gle ra dio activ e sp otw as ob serv ed , [I8 F]h alo perid ol p ro ba bly acc ou nts fo rth e r emain in g r ad io ac tiv ity a s w ell.

DISCUSSIONIn th e cu rren t stu dy , ev id en ce fo r th e sp ecific labe lin gin vivo of neuroleptic binding sites in m ouse brain w ith[1 8F ]h alo pe rid ol h as b ee n p re se nte d. B ec au se d op am in e

recep to rs are ab un da nt in the striatum an d relativ ely rarein the cerebellum (22), the dose-dependent decrease inthe relative concentration in the striatum and in thestria tum-to -c ere be llum c on ce ntra tio n ra tio is c on siste nt

STRIATUM

001 01 10 10 10DOSE O F H A LO P ER IOO L

1000

F IG . 2 . R ela tiv e c on ce nt ra tio ns o f | lt !F | h alo pe rid ol in s tria tum a ndcerebellum of m ice at 1 hr after injection, as a function of adm inis te re d d os e o f h alo pe rid ol. E rro r b ars re pre se nt s ta nd ard e rr or o ft he mean .

| "F | H A LO P ER ID O L

001 0.1 1.0 10 100 1000HALOPERIDOLLXISE(g/kg)F IG . 3 . S tr ia tum-t o-c er eb ellum ra dio ac tiv it y c on ce nt ra tio n r atio sin m ic e a t 1 h r a fte r in je ctio n o f [G -3 H]- a nd o f [1 8F ]-h alo pe rid ol a sa f un ct io n o f a dm in is te re d d ose o f h alo pe rid ol . E rr or b ar s r ep re se nts ta nd ard e rro r o f t he me an .

with r ec ep to r-media te d l oc aliz ati on o f [ I8F] ha lope rid olin the striatum (Figs. 2 and 3). At haloperidol doses of< 1 M g/kgthat is, at doses below those necessary tosat ur at e spec if ic b ind ing s it es a r el at ive ly l arge f ract ionof haloperidol in brain is specifically bound and istherefore localized in the striatum . A s the haloperidoldose is increased (1-100 Mg/kg), approaching andeventually exceeding that necessary to saturate thespe cific b in din g sites, an inc rea sin g p ro portion o f haloperidol is bound nonspecifically. A t high haloperidoldoses (> 100 M g/kg)that is, at doses that greatly ov-e rs at ur at e t he speci fi c b ind ing s it es nonspeci fi c b ind ingp re domin ate s, w ith a n ota ble a bs en ce o f s ele ctiv e stria ta !lo ca liz atio n o f F -1 8. T his is b ec au se n on sp ec ific b in din gis generally considered to be as likely to occur in thecerebellum as it is in the striatum , since neurolepticsre ad ily lo ca liz e in b io lo gic al m embra ne s b ec au se o f th eirh igh lip id s olubi lity ( 23 ,26). T hi n- la ye r c hr oma togr aphyof F-18 in m ouse brain suggests that m ost of the radioactivity represented intact [18F]haloperidol. The app aren t ab sen ce of a ny sub stan tial ex tra-h ep atic m etabolism of haloperidol (35,39,51,52) and the rapid bloodclearance (53) and excretion (35,39,51,52) of halop erid ol m eta bo lite s, a re c on siste nt w ith th is s up po sitio n.B ecau se the carb on -flu orine b on d is the sin gle stron gestb on d fo rm ed b y carbo n (5 4), sp on tan eo us d e-flu orina -tion o f h alo perid ol in v iv o is h ig hly un likely.The results obtained with [G-3H]haloperidol arem arkedly different from those obtained w ith [1X F]halo perid ol. A t all h alo perid ol d oses, th e re lativ e con centration of tritium in the striatum and in the cerebellummaintains a constant low value of approximately 2.0.Even at low haloperidol doses, w here dem onstrableb in din g to sp ecific rece ptors is exp ected to occ ur, selective striatal localization of tritium is not observed.Thin-layer chrom atography of tritium in m ouse brainsuggests that practically none of the radioactivity represented haloperidol. M oreover, the relative concen-

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ZANZONICO, B IG LER, AND SCHMALLtration of tritium in m ouse brain 1 hr after the adm ini st ra ti on o f 3H2O (1.1) ( unpubl is hed r esul ts ) compar esw ith th at 1 h r a fte r th e a dm in istra tio n o f [G -3H]h alo -pe ri do l ( 1.9) . I t appear s, t he re fo re , t ha t t he r ad io ac ti vi tyi n v ivo f ol low ing the admini st ra ti on o f [G-3H]ha lope r-id ol w as la rg ely "fre e" tritium, th at is, tritia te d w ate r.T hu s, [G -3H] h alo pe rid ol is n ot u se fu l fo r th e sp ec ificla be lin g in v iv o o f n eu ro le ptic b in din g s it es b ec au se o fth e lability of the tritium atom s. A critic al, but oftentim es ig no re d, c on sid era tio n in su ch a n e xp erim en t isc le arly th e s ta bilit y o f th e tra ce r to s po nta neou s ra dio -chemical degradation (e.g. ,de t ri ti at ion) under the actua lexper imenta l condi tions .[G -3H]halope ri do l i s p repar ed commerc ia ll y by catalytic exchange in the presence of tritiated water.Though nomina ll y "gene ra ll y l abel ed ," t he p ri nc ip a l s it eo f la be lin g is p re sumab ly th e mthyl n eroup in the apos it ion to the car bony l f unc ti on . The ca rbonyl f unct iontend s to in crease the acidity of the a-h ydrogen atom s(55). In order to determ ine w hether its lability in v ivow as d ue sim ply to th e a cid ity o f th e a -h yd ro ge n a toms,[G -3H]h alo pe rid ol w as in cu ba te d a t 3 7 Cfo r 1 h r a tv ario us h yd ro gen-io n con centra tio ns (pH 3 ,7 , a nd 1 0).T he ra dio ch em ic al p urity , a s d ete rm in ed b y TLC , w asin a ll i ns ta nc es c ompara ble to th e s pe cifie d v alu e (9 7%)fo r th e c ommerc ia l p re pa ra tio n (m ain ta in ed a t 4C ).Cons is te nt w ith i ts u tility in re cepto r-b in din g a ss ay s inv it ro , conducted under physiolog ic cond i tions (37C,pH7 .4 ), t he de- tr it ia ti on o f [G-3H]ha lope ri do l i n v ivo i s nots imp ly a tempe ra tu re - o r pH-d ep en dent p ro ce ss .Based princ ipa lly on the d if feren tial b ind ing aff in i ti eso f dopaminergic l igands , the ex is tence of d is tinc t c lasses ,o r sub se ts , o f dopamine r eceptor s has been hypo thes ized(2 2,5 6-5 8). F or e xamp le, th e p uta tive "d op am in e-2(D 2)" receptor, w hich exhibits a thousand tim es thea ffin ity fo r a nta go nis ts a s fo r a go nis ts , h as b een imp licat ed in the pathogenesi s o f s ch izophr en ia ( 13 -15,22 ),as w ell as in the antipsy chgtic effect of neurole ptics(5,22,26) . The dose- dependen t s igmoida l dec rease inth e re la tiv e c on ce ntra tio n o f- [1 8F ]h alo pe rid ol in th es tr ia tum and in the s tr ia tum- to -cerebel lum concen tr at ionra tio a pp ea rs to b e con ceptu all y c on sis te nt w ith a s in glec la ss o f acces si bl e b inding s it es i n v ivo . Mu lt ip le c la ss eso f a cc es si ble b in din g s ite s in v iv o would b e exp ec te d toy ie ld a d os e-re sp on se curv e (i.e ., t is su e con centra ti onaga in st lo g d os e) c on sis tin g o f a n umber o f d is tin ct s igmo idal component s. Ea rl ie r s tud ie s, t hough suggest iv eo f a sin gle c la ss o f b in din g s ite s in v iv o, h av e n ot u nambiguous ly iden ti fied the shape of the dose-r esponse curveb ec au se o f th e lim ite d ra ng e (> 1 Mg /k g) o f n eu ro le pticd os es s tu die d (2 7, 29 ,3 1,3 2). T he curre nt s erie s, w h ic hinc ludes ha lope ri do l doses a s l ow as 0 .01 Mg /kg, y ie ld edan u nambig ou sl y s igmoid al d os e-re sp on se curv e, th ussu gg estin g th e e xiste nc e o f a sin gle c la ss o f a cc ess ib leb in din g s it es in v iv o.In c on tra st to th e stria tum, d op am in e re ce pto rs a re

re la tiv ely d efic ie nt in th e c ere be llum (2 2). H ollt e t a l.(2 7), H ollt a nd S ch ub ert (2 9), a nd Kuh ar et a l. (3 1), a llfo un d a ma rk ed d os e-d ep en dent d ec re as e in th e s tria ta !c on ce ntra tio n o f tritia te d sp iro pe rid ol, b ut d id n ot o bs erv e any d ec re as e in th e c er eb ella r c on centra tio n. It isunl ik ely, t he re fo re , t ha t t he do se -dependen t decr ea se inth e re la tiv e c on ce ntra tio n o f [1 8F ]h alo pe rid ol in th ec ere be ll um (F ig . 2 ) is r ec ep to r-media te d. T ew son e t a l.(59) found that pretreatm ent of a m onke y w ith a ph arm ac olo gie d os e o f h alo pe rid ol re du ce d th e fra ctio n o fno-carr ie r- added [18F]haloper ido lex tr ac ted by the bra indur ing a s ingl e cap il la ry t rans it f ol low ing inj ec ti on intoth e in te rn al c aro ti d a rte ry . B e caus e c ere bra l b lo od fl oww as not altere d, the o bserved decrease in e xtractionfra ctio n (i.e ., from 0 .7 to 0 .4 ) w as e xp la in ed b y p ostula tin g th at [I8 F]h alo pe rid ol c ompe te s w ith e xc ess u n-la be le d h alo pe rid ol fo r a c arrie r-m ed ia te d tra nsp ortsy stem a t th e b lo od -b ra in b arrie r. T his p ostu la te d sa tu ra ble c ompo ne nt o f h alo pe rid ol tra nsp ort in to b ra inc ou ld a lso e xp la in th e d ose -d ep en de nt d ec re ase in th ere la tiv e con centra ti on o f [I8 F]h alo pe rid ol in th e c erebellum. Consistent wi th thi s hypothes is i s the f ind ing thatth e c ere be lla r c on ce ntra tio n o f h alo pe rid ol in d og s d ecreased by nearly 50% a s the h aloperidol dose w as increased from 40 to 630 M g/k g (37 ).T he stria ta l a nd th e c ere be lla r c on ce ntra tio ns o f h alo pe rid ol, a s in dic at ed i n T ab le 1 , a re mu ch g re ate r th anth ose of other neu roleptics, in cluding spiroperido l(2 7- 32 ), /7 -b romo sp ir op er id o ( 33 ,3 4), a nd p imoz id e(2 8,3 0,6 0). T he s tr ia ta l a nd th e c er eb ella r c on ce ntr ati on s a re n ot in co ns is te nt w ith th e who le -b ra in con cent ra ti on s det erm ined by t is su e d is tr ibut ion s tudi es i n r at susing either 4'-fluorobutyrophenone-[2'-3H]haloperidol(3 7- 39 ) o r [ 18F]ha lo pe rid o ( 5 3), a nd b y e xte rn al s cin -t ig raphy in dog s and in monkeys u sing [ 18F]ha lope ri do l(45 ,53 , unpubli shed data). For a given level o f s ta ti st ica laccuracy , the grea ter b rain concen tr at ions of haloper ido lw ill p ermit re du ctio n o f th e d os e o f ra dio ac tiv ity , o r th ed ura tio n o f d ata a cq uisitio n, fo r th e d ete rm in atio n b yPET o f r eg iona l r eceptor concen tr at ions . A lt er na ti ve ly ,fo r a g iv en d ose o f ra dio ac tiv ity , th e g re ate r b ra in c onc en tra tio ns o f h alo pe rid ol w ill s erv e to in cre as e th e s tatistic al a cc ura cy o f re gio na l re ce pto r c on ce ntra tio nm ea surem ents. A s ind icated in T able 2, the brain-to-b lood concent ra ti on r at io s a re l ik ew i se much g reat er f orh alo pe rid ol (3 9,5 3,6 1 ) th an f or o th er n eu ro le ptic s, inc luding p imozide ( 61 ), t ri fl uper idol ( 67 ), b romperi do l(53 ,62), and spiroper ido l (63). This wi ll serve to increasefurther the statistic al accura cy of regiona l recep torconcen tr at ion measur ement s by r educ ing the co rr ec ti onf or t he vascul ar component o f r ad io ac ti vi ty w it hin b ra intissue.If o ne a ssume s th at stria ta l a nd c ere be lla r ra dio act iv it ie s r ep re sent t ot al and f ree l ig and, r espect iv ely, t hemax imum tot al -t o- fr ee ( i. e. , s tr ia tum-to- ce rebel lum)h alo pe rid ol c on centra tio n ra tio in v iv o ( 4.6 , T ab le 1) is

412 THE JOURNAL OF NUCLEAR MEDICINE


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BASIC SC IENCESR AD IO CH EM IS TR Y A ND R AD IO PH ARMA CE UT IC AL S

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Z AN ZO NIC O, B IG LE R, A ND S CHMA LL

TABLE 2. BRAIN-TO-BLOOD CONCENTRATION RATIOS OF VARIOUS RADIOLABELEDEUROLEPTICSRadioligand4'-fluorobutyrophenone-[2'-3H]-haloperidol4'-fluorobutyrophenone-[2'-3H]-haloperidol[18F]haloperidol1-(4,4)-bis-


8/9

BASIC SC IENCESRAD 1OCHEM IS TR Y AND RAD IO PHARMACEU TI CA LS

REFERENCES/. B ERNHEIMER H , B IRKMAYERW , HORNYKIEW ICZO , e tal: Brain dopam ine and the syndrom es of Parkinson andHun ti ng to n./ yV eu ro /S ci 2 0:4 15 -4 55 , 1 97 32. HORYNKIEW ICZ O : D op am ine (3 -h yd ro xy ty ra min e) an db rain fu nc tio n. P harm R ev 1 8:9 25 -9 64 , 1 96 63. D uvoiSlN R: Parkinsonism . C IBA Clinical Sym posia 28:1-29,19764. K LAWA NS H L, P AU LSO N GW, RIN GEL SP, et al: T he useo f L -DOPA in t he p re symptoma ti c d et ec ti on o f Hunt in gt on 's

c ho re a. Adv Neur al 1 :2 95 -3 00 ,1 9735. T OLOS A E S, S PARS ER S B: A pomor ph in e in H un tin gto n'schorea : Cl in ica l obse rva tions and theo re tica l cons ide ra t ions,Life Sc i 15 :1371-1380,19746. SCHIE LE BC, G ALLANT D , SIM PSON G , et al: N eurologics yn dr om es a ss oc ia te d w ith a nti ps yc ho ti c- dr ug u se . A ' E ng lJ M ed 289:20-23, 19737 . KLAWANS HL, J R: T he p ha rmac ol og y o f t ar div e d ys ki ne si as .A m J P sychiatry \ 3 0:82-86, 19738. JE STE D V, W YA TT R J: C hanging epidem iology of tardivedy skin esia : A n o ver v ie w. Am J P sy chia try 1 38 :2 97-3 09 ,19819. BA RB AC CIA M L, TR ABU CC HI M : Tardive dyskinesia: Ab io lo gic al a pp ro ac h. I n N eu ro ch em is try a nd C lin ic al N eurology, N ew York, A lan R . L iss, 1980, pp 181-19310. GOETZ CG, W EINER W J, NAUSIED A PA, et al: Tardived ys ki ne si a: P ha rm ac olo gy a nd c li nic al imp lic at io ns . ( "/ // /Neu ro ph arma co l 5 :3 -2 2, 1 98 2//. BARCHAS JD, AKIL H, ELLIOTT GR, et al: Behavioraln eu ro ch em istry : N euro reg ulato rs an d b eh av io ra l sta te s.S ci en ce 2 00 :9 64 -9 73 , 1 97 81 2. MATTHYSSE S , L IP INSK I J : B io ch em ic al a sp ec ts o f s ch iz op hren ia. A nn R ev Med 2 6:55 1-5 65, 1 97 51 3. S NYDER SH: T he d op am in e h yo pth esis o f sc hiz op hre nia :Focus on the dopamine receptor. Am J Psychiatry 133:197-202,197614. M ELTZER HY, STAHL SM : The dopamine hypothesis ofschizophrenia: A review . S chizophrenia B ull 2:19-76,19761 5. SNYDER SH: Dop am in e r ec ep to rs , n eu ro le pti cs , a nd s ch izo ph ren ia. Am J P sy ch iatry 1 38 :4 60 -46 4, 1 98 11 6. SNYDER SH, BENNETT JP, J R: N eu ro tr an sm itt er r ec ep to rsin th e b rain: B io ch em ic al id en tifica tio n. A nn R ev P hy siol3 8: 15 3- 175, 1 97617 . W IL LIAMS L T, L EVKOW IT Z R J: R ece pto r B in din g S tu die si n Adr en er gi c Pha rmac ol og y, N ew Y or k, R av en P re ss Boo ks ,L td , 1 97 818. YAMAMURA HI, ENNA SJ, KUHAR MJ (Eds): Neurot ra nsm it te r Re ceptor B inding , New Yor k, Ra ven Pr es s Book s,L td , 1 97 81 9. COOPER JR , B LOOM RE, ROTH RH: T he B io ch em ic al B as iso fN eu ro ph arma co lo gy , N ew Y or k, O xf or d Uni ve rs it y P re ss ,I ne , 1 97 8, p p 6 0- 71

20 . PHELP S ME: Emissio n c om pute d to mo gra ph y. S em in N uc M ed 7 :33 7-3 65, 1 97 72 1. R AICHL E ME : Q uan tita tive in vivo a uto ra dio gra ph y w ithpositron em ission tom ography. B rain R es R ev 1:47-68,197922 . S EEMAN P : B r ain d op am in e r ec ep to rs . P ha rm ac ol R ev 3 2:2 29 -3 13 , 1 98 02 3. S EEMAN P , B IALY HS: T he s ur fa ce a ct iv ity o f t ra nq ui li ze rs .B io ch em Pha rmac ol 1 2: 11 81 - 11 91 , 1 96 324 . S EEMAN P : Th e m em bra ne a ctio ns o f a nesth etic s a nd tr anq uil iz ers . P ha rm Rev 2 4: 58 3- 65 5 1 97 225. SEEMA N P, S TA IM AN A, CH AU -W ONG M : T he nerve imp ulse -b lo ck in g a ction o f tra nq uiliz ers, a nd th e b in din g o f

n eu ro le pt ic s to s yn ap to some membr an es . J P ha rm ac ol E xpT he r 1 90 :1 23 -1 30 , 1 97 42 6. S EEMAN P : Ant i-s ch iz op hr en ic d ru gs -M embr an e r ec ep to rs it es o f a ct io n. B io ch em Pha rm ac ol 2 6: 17 41 -1 74 8, 1 97 72 7. HL LT V, C ZLONKOWSK I A , HERZ A : T he d em on stra tio ni n v iv o o f s pe ci fi c b in di ng s it es f or n eu ro le pt ic d rugs i n mous ebra in . B ra in R es 1 30 :1 76 -18 3, 1 97 728. LADURON P , LE YSE N J: Specific in vivo binding of neurol ep ti c d ru gs i n r at b ra in . B io ch em Pharmacol 2 6: 10 03 -1 007,19772 9. H LL TV , S CHUBERT P :D emo ns tra tio n o f n eu ro lep tic rece pto r site s in m ou se b rain b y au to ra dio grap hy . B rain R es151:149-153,197830. LADURON PM, JA NSSE N P FM , LE YSE N JE : Spiperone. Al ig an d o f c ho ic e f or n eu ro le pt ic r ec ep to rs . 2 . Regi on al d is tr ibu tion and in v ivo d isp lacemen t o f neurolep t ic d rugs . BiochemPha rmac ol 2 7: 31 7- 32 1, 1 97 831. KU HAR M J, M UR RIN LC , M ALO UF A T, et al: D opam iner ecepto r b ind ing in v ivo : The feas ib il ity o f au to rad iog raph ics tud ie s . L i fe Sc i 22 :203-207 ,197732. LE FUR G, GUILLOUX F, UZAN A: In vivo blockage ofdo pamine rg ic re ce pto rs from d iffe ren t rat b rain re gio ns b yc la ssica l an d aty pica l n eu ro le ptics. B io ch em P ha rm aco l2 9: 26 7- 270, 1 98033. K ULM ALA H K, H UA NG CC , D IN ER STEIN RJ, et al: Spec if ic in v ivo b ind ing o f 77Br-p -b romosp irope rido l in ra t b ra in :A p ote ntial to ol fo r gamm a ra y im ag in g. L ife S ci 2 8:1 91 1-1916,198134. F RIEDMAN AM, HUANG CC, KULMALA H A, et al: T he useo f r ad io br om in at ed p -b romo sp ir op er id ol f or x -r ay im ag in go f d op am in e r ec ep to rs . I nt J N ucMe d B io l 9 :5 7- 61 , 1 98 23 5. B RAUN GA, P oos G I, S OUDIJN W : D istr ib utio n ex cre tio na nd met ab oli sm o f n eu ro le pti cs o f t he b uty ro ph en on e ty pe .Pa rt I I. D i st ri bu ti on , e xc re ti on a nd me ta bo li sm o f h al op er id olin S prag ue-D aw le y rats. E ur J P ha rm ac ol 1 :5 8-6 2, 1 96 73 6. S OUDIJ N W , VAN W IJNGAARDEN I: A ra pid a nd c on ve nien tme thod for t he s yn th es is o f l ab el ed t er ti ar y am in es . J Labe ll edCom p 4 :1 59 -1 63 , 1 96 837. JANSSEN PAJ, SOUDIJN W , VAN W IJNGAARDEN I: Pi-

moz id e, a ch em ica lly n ov el, h ig hly p oten t a nd o rally lon g-a ct in g n eu ro le pt ic d ru g. 3 . Regi on al d is tr ib ut io n o f p imozi dea nd o f h alo perido l in the do g b ra in . A rzn eim -F orsc h (D rugRes ) 1 8: 28 2- 28 7, 1 96 83 8. JANS SEN PA, A LL EW IJN FT: T he d is trib utio n o f th e b uty -rophenones ha loper ido l, t ri flupe rido l, moperone , and c lo f lu -pe ro l in rat s, and i ts relat ionsh ip wi th the ir neuro lep tic ac tivi ty .A rzeim -F ors ch (D ru g R es) 1 9:1 99 -20 8, 19 6939. LEWI P J, H EYK AN TS JJ, A LLEWIJN F T: D istribution andmeta bo lism o f n eu ro le pt ic d ru gs . I. P ha rm ac ok in eti cs o f h alo pe ri do l. A rz eim -For sc h (D ru g R es ) 2 0:9 43 -9 48 , 1 97 04 0. NAY LOR R J, O LL EY JE : T he d istr ib utio n o f h alop erido l inrat b rain. B rJ P harm aco l 3 6:20 8P -2 09P , 1 97 941. HOW LETT DR, NAHORSKI SR: A comparative study of[ 3H ]ha lo pe ri do l a nd [ 3H ] sp ir op er id ol b in di ng t o r ec ep to rson rat cerebral m em branes. FE BS Letters 87:152-156,19784 2. DEMENGE P , FEUERST EIN C , MOUCHET P , e t a l: S te reo -s pe cif ic b in din g o f 3H- ha lo pe ri do l i n r at d or sa l s pi na l c or d.E ur J P ha rm ac ol 6 6:1 17 -12 0, 19 8043. K OOK C S, R EED MF, D IG EN IS G A: P reparation of [18F ]-h alop erid ol. J M ed C hem 1 8:5 33 -5 35, 1 97 54 4. S CHMAL L B , B IG LER RE: R ad io la beled d ru gs: U se o f po sitr on -emit ti ng r ad io nu cli de s. I n R ad io ph arm ac eu tic al s:S tr uc tu re -A ctivity R ela tio nsh ip s, R P S pe nc er (E d). N ewYor k, G ru e& S tra tto n, In e, 1 98 1, p p 7 69 -8 0045. BIG LE R RE , K OSTIC K JA , W OODARD HQ, et al: U se of aco ll ima tec i sou rce o f fas t neut rons to measu re ma lignant tumor

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ZANZONICO, BIGLER, AND SCHM ALLe le ctr oly te e xc ha ng e. I EEE T ra ns NucSc i NS-24 :559 -562,197746. JANSSEN PAJ, VAN DE WESTERINGH C, JAGENEAUAHM , et al: C hem istry and pharm acology of C NS depress an ts r el at ed t o 4 -( 4- hydr oxy 4 -p heny l) -p ip er id in o) b ut yr o-p he no ne . P ar t I: S yn th es is a nd s cre en in g d ata i n m ic e. J Me dP harm C hem 1:281-297, 195947. LAUGHL IN JS, M AMOCOS JP , TILBUR Y R S: Isochronouscyclot ron in stal la tion for rad ionucl ide p roduc tion . Rad io logy93:331-337,196948. TIL BU RY R S, D AH L JR , M AMOCOS JP , et al: F luorine-18production for m edical use by helium -3 bom bardm ent ofw ater. Inter J A ppi R ad Isotopes 21:277-281, 19704 9. G LOWIN SK I J, IV ER SEN L L: R eg ion al stu dies o f c ate ch ol-amin es i n t he r at b ra in I . T he d is po si tio n o f [ 3H ]n or ep i-n ep hri ne , [ 3H ]d op am in e, a nd [3H] do pa in v ar io us r eg io ns o fth e bra in . J N eu ro ch em 1 3:65 5-6 69, 1 96 65 0. WOODARD HQ, B IGLERRE , FREED B , e t a l: E xp res sio n o fti ss ue i so to pe d is tr ib ut io n. J N ucMe d 1 6: 95 8- 95 9, 1 97 55/. SO UD IJN W , V AN W IJN GA AR DE N I, A LLEWIJN G : D istrib ution , e xc retio n a nd m eta bo lis m o f n eu ro lep tic s o f th ebutyrophenone type. P art I. E xcretion and m etabolism ofha loper ido l and n ine rela ted bu ty rophenone -de riva tives in theW istar rat. E ur J P harm acol 1:47-57, 1967

52. F OR SM AN A , HMAN R : P harm acokinetic studies on halo perid ol in m an . C urr T he r R es 2 0:31 9-3 36, 1 97 653. D IG EN IS G A, V IN CENT SH , KOOK C S, et al: T issue distribution studies of [18F]haloperidol , [ l8F]- |8-(4-f luorobenzoyl)p ro pi on ic a cid , a nd [ 82Br] br ompe ri do l b y e xt er na l s cin tig -raphy. J P harm S ci 70:985-989, 19815 4. SHARPE AG : T he p hy si ca l p ro pe rti es o f t he c ar bo n- fl uo rin eb on d. I n C ib a Fou nd ati on Sympo si um o n Car bo n-F lu or in eCompo un ds : B io ch em is tr y, a nd B io lo gi ca l A ct iv iti es , N ewYor k, A ss oc ia te d S ci en tif ic P ub li sh er s, 1 97 2, p p 3 3- 5455. M ORRISON RT, BOYD RN: Organic Chem istry, 3rd ed,B os to n, A lly n a nd B ac on , I ne , 1 97 3, p p 7 01 -7 0356. SN YD ER SH , BUR T D R, C RE ESE I: The dopam ine receptoro f t he m ammali an b ra in : D emon st ra tio n o f b in di ng t o a go ni st

an d a nta go nist s ta te s. N euro sc i S ym p 1 :2 8-4 9, 1 97 657. K EB AB IAN JW , C ALN E D B: M ultiple receptors for dopam in e. N atu re 27 7:93 -9 6, 1 97 95 5. COSTALL B , NAYLOR R J: T he h yp oth es es o f d iffe re nt d op am in e r ec ep to r m ec ha ni sm s, L if e S ci 2 8: 21 5-2 29 , 1 98 159. TEWSON TJ, RAICHLE ME, WELCH MJ: Preliminarys tud ie s wi th [18F]ha loper ido l: A radiol igand fo r in v ivo s tud ie sof do pam in e rec ep to rs. B ra in R es 19 2:29 1-2 95, 1 98060. BA UD RY M , M ARTR ES M P, SC HW AR TZ JC : I n vivo bindi ng o f 3H- pimo zi de i n mo us e s tr ia tum: E ff ec ts o f d op am in ea go ni st s a nd a nt ag on is ts . L if e S ci 2 1:1 16 3-1 17 0, 1 97 761. G IVA NT Y, SH AN I (M ISH KIN SKY) J, G OLD HAB ER G , eta l: P ha rm ac ol og y o f th re e m ammot ro pic b ut yro ph en on es inth e ra t. A rch In t P ha rm ac ody n 2 05:3 17-3 27 , 1 97 362. VIN CEN T SH , SH AM BHU M V, D IG EN IS G A: Synthesis of[82Br ]b romper ido l and p rel iminary t is sue d is tr ibu tion s tud ie sin the rat. J M ed C hem 23:75-79, 198063. FOWLE R JS, ARN ETT C D, W OLF A P, et al: [' 'C ]Spirop-e ri do l: S yn th es is , s pe ci fi c a ct iv ity d et ermin ati on , a nd b io -d is tr ib ut io n in m ic e. J N ucMe d 2 3:4 37 -4 45 , 1 98 264. LE YSEN JE , G OMME RE N W , LA DU RO N PM : Spiperone:A l ig an d o f c ho ic e fo r n eu ro le pt ic r ec ep to rs . 1 . K i ne ti cs a ndch aracte ristic s o f in v itro bin din g. B ioc hem P ha rm aco l 2 7:3 07 -3 16 , 1 97 865. MAR TR ES MP, B AUDRY M , S CHWARTZ JC : C haracteriz at io n o f 3H-d ompe rid on e b in di ng o n s tr ia ta l d op am in e rec ep to rs . L if e S ci 2 3: 17 81 - 17 84 , 1 97 86 6. L ADURON PM , LEY SEN JE: Dompe ri do ne , a s pe ci fi c in v itr odop am ine ant ag on is t, d ev oi d o f i n v iv o c en tr al d op am ine rg ica ct iv ity . B io ch em Pha rm ac ol 2 8: 21 61 -2 16 5, 1 97 967. B AK HLE YS, VA NE JR: Pharm acokinetic function of thep ulmo na ry c irc ula ti on . P hy sio l R ev 5 4:1 00 7-1 04 5, 1 97 468. B ROWN EA: The localization, m etabolism , and effects ofdrugs and toxicants in lung. D rug M etab Rev 3:33-87,197469. T EW SON T J, W EL CH M J: P reparation of fluorine-18 arylfl uo rid es : P ip er id yl t ria ze ne s a s a s ou rc e o f d ia zo ni um s al ts .J C hem Soc C hem C om m 1149-1150, 1979

May 28-30, 1983

Hawaii ChapterSoc iety o f Nuc lea r Med icin e6 th Annua l Mee tin gHya tt K uilim a Hote l K ah uku, O ahu, H aw aiiThe Hawa ii C hap te r o f th e Socie ty o f Nuclear Medi ci ne w ill h ol d it s 6 th Annua l Meeti ng on May 28 -30, 1983a t t he Hyat tKu ilima Ho te l lo ca ted on Oahu 's magn if ic en t no rt h sho re .Guestspeakersfor th is year' s meet ing areW i l Nelp ,M.D. ,ErnestGarc ia , Ph.D.,Phi l ip Mat in , M.D.and MichaelK ipper ,M.D.Topicsto be addressedat th is Memor ial DayW eekendconferenceinc lude cl in ica l and technica l aspects of ro ta t iona l tomography,quan ti fi ca ti on o f t ha ll ium imag ing , uses o f monoclona l an ti bod ies , pu lmonary , bone and ln-111ox ine labe led WBCimag ing . Con ti nu ing Educa ti on and VOICE cred it s w il l be avai lab le for pa rt ic ipants.For further information contact: Patrick McGuiganThe Hono lu lu Medi ca l G roupDept . o f Nuclear Medi cin e550 Sou th Bere tan ia S tree tHonolulu, Hawai i 96813

41 6 THE JOURNAL OF NUCLEAR MEDICINE

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P. B. Zanzonico, R. E. Bigler, and B. Schmall- Neuroleptic Binding Sites: Specific Labeling in Mice with [^18]Haloperidol, A Potential Tracer for Positron Emission Tomography