Skip to main content
Log in

Stereoselective binding of 11C-raclopride in living human brain — a search for extrastriatal central D2-dopamine receptors by PET

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

The selective D2-dopamine receptor antagonist raclopride and its pharmacologically inactive (R)-enantiomer FLB472 were labelled with 11C and used in a study with positron emission tomography to examine the stereoselectivity of 11C-raclopride binding to central D2-dopamine receptors in three healthy men. After the injection of 11C-raclopride, there was a high accumulation of radioactivity in the dopamine-rich basal ganglia, whereas after the injection of 11C-FLB472 there was no such accumulation of radioactivity. Thus, the binding of 11C-raclopride is stereoselective. Distribution ratios [radioactivity in a brain region/“free” (not protein-bound) radioactivity in plasma] were calculated for the two enantiomers to study regional differences in the accumulation of radioactivity. The distribution ratios in white matter were similar for the two enantiomers. In the putamen, a three to four-fold higher distribution ratio was found for 11C-raclopride than for 11C-FLB472, reflecting the presence of specific binding of 11C-raclopride binding to D2-dopamine receptors in the basal ganglia. In the temporal and frontal cortices the distribution ratios were, however, only a few per cent higher for 11C-raclopride than for 11C-FLB472, indicating that if D2-dopamine receptors are present in the human neocortex, then their density is indeed very low.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bannon MJ, Roth RH (1983) Pharmacology of mesocortical dopamine neurons. Pharmacol Rev 35:53–68

    Google Scholar 

  • Bergström M (1982) Performance evaluation and improvements of quantitation accuracy in transmission and positron emission computer assisted tomography. Thesis. Karolinska Institutet, Stockholm

    Google Scholar 

  • Bergström M, Boethius J, Eriksson L, Greitz T, Ribbe T, Widen L (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136–141

    Google Scholar 

  • Bischoff S (1986) Mesohippocampal dopamine system. Characterization, functional and clinical implications. In: Isaacsson RL, Pribram KH (eds) The hippocampus, vol 3. Plenum Press, pp 1–30

    Google Scholar 

  • Björklund A, Lindvall O (1984) Dopamine-containing systems in the CNS. In: Björklund O, Hökfelt T (eds) Handbook of chemical neuroanatomy. Classical transmitters in the CNS, vol 2, part I. Elsevier, Amsterdam, pp 55–122

    Google Scholar 

  • Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144

    Google Scholar 

  • Craig DP (1976) Discriminating interactions between chiral molecules. Top Curr Chem 63:1–48

    Google Scholar 

  • Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483

    Google Scholar 

  • Ehrin E, Gawell L, Högberg T, dePaulis T, Ström P (1987) Synthesis of (methoxy-3H) — and (methoxy-11C)-labelled raclopride — specific dopamine-D2 receptor ligands. J Labelled Comp Radiopharm 24:931–939

    Google Scholar 

  • Farde L, Ehrin E, Eriksson L, Greitz TY, Hall H, Hedström CG, Litton JE, Sedvall G (1985) Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 82:3863–3867

    Google Scholar 

  • Farde L, Hall H, Ehrin E, Sedvall G (1986) Quantitative analysis of dopamine-D2 receptor binding in the living human brain by positron emission tomography. Science 231:258–261

    Google Scholar 

  • Farde L, Halldin C, Stone-Elander S, Sedvall G (1987a) PET analysis of human dopamine receptor subtypes 11C-SCH 23390 and 11C-raclopride. Psychopharmacology 92:278–284

    Google Scholar 

  • Farde L, Wiesel F-A, Hall H, Halldin C, Stone-Elander S, Sedvall G (1987b) No D2 Receptor Increase in PET Study of Schizophrenia. Arch Gen Psychiatry 44:671–672

    Google Scholar 

  • Farde L, Wiesel F-A, Halldin C, Sedvall G (1988a) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry (in press)

  • Farde L, Wiesel F-A, Jansson P, Uppfeldt G, Wahlen A, Sedvall G (1988b) An open label trial of raclopride in acute schizophrenia — confirmation of D2-dopamine receptor occupancy by PET. Psychopharmacology 94:1–7

    Google Scholar 

  • Giacomini J, Nelson W, Theodore L, Wong F, Rood D, Giacomini K (1985) The pharmacokinetics and pharmacodynamics of d- and dl-verapamil in rabbits. J Cardiovasc Pharmacol 7:469–475

    Google Scholar 

  • Glowinski J, Tassin GP, Thierry AM (1984) The mesocortico-prefrontal dopaminergic neurons. Trends Neurosci 18:415–418

    Google Scholar 

  • Hall H, Wedel I (1986) Comparisons between the in vitro binding of two substituted benzamides and two butyrophenones to dopamine-D2 receptors in the rat striatum. Acta Pharmacol Toxicol 58:368–373

    Google Scholar 

  • Hall H, Farde L, Sedvall G (1987) Human dopamine receptor subtypes — in vitro binding analysis using 3H-SCH 23390 and 3H-raclopride. J Neural Transm (in press)

  • James A, Roos M (1975) Minuit. Comput Physics Commun 10:343–367

    Google Scholar 

  • De Keyser J, De Backer J-P, Eginger G, Vauquelin G (1985) Regional distribution of the dopamine D2 receptors in the mesotelencephalic dopamine neuron system of human brain. J Neurol Sci 71:119–127

    Google Scholar 

  • Köhler C, Hall H, Ögren S-O, Gawell L (1985) Specific in vitro and in vivo binding of 3H-raclopride. A potent substituted benzamide drug with high affinity for dopamine D2 receptors in the rat brain. Biochem Pharmacol 34:2251–2259

    Google Scholar 

  • Köhler C, Radesäter AC (1986) Autoradiographic visualization of dopamine D-2 receptors in the monkey brain using the selective benzamide drug (3H) raclopride. Neurosci Lett 66:85–90

    Google Scholar 

  • Litton J, Bergström L, Eriksson L, Bohm C, Blomqvist G, Kesselberg M (1984) Performance study of the PC-384 positron camera system for emission tomography of the brain. J Comput Assist Tomogr 8:74–87

    Google Scholar 

  • Martes M-P, Bouthenet M-L, Sales N, Sokoloff P, Schwartz J-C (1985) Widespread distribution of brain dopamine receptors evidenced with (125I)iodosulpride, a highly selective ligand. Science 228:752–754

    Google Scholar 

  • Mazziotta JC, Phelps ME, Plummer D, Kuhl D (1981) Quantitation in positron emission computed tomography: 5. Physical — anatomical effects. J Comput Assist Tomogr 5(5):734–743

    Google Scholar 

  • Olanoff L, Walle T, Walle K, Cowart D, Gaffney T (1984) Stereoselective clearance and distribution of intravenous propranolol. Clin Pharmacol Ther 35:755–761

    Google Scholar 

  • Pennkopf E (1963) Atlas der topographischen und angewandten Anatomie des Menschen. Erster Band: Kopf und Hals. 106. Urban und Schwarzenberg, Munich

    Google Scholar 

  • Sedvall G, Farde L, Persson A, Wiesel F-A (1986) Imaging of neurotransmitter receptors in the living human brain. Arch Gen Psychiatry 43:995–1005

    Google Scholar 

  • Sedvall G, Ehrin E, Farde L (1987) Stereoselective binding of 11C-labelled piquindone (Ro22–1319) to dopamine-D2 receptors in the living human brain. Hum Psychopharmacol 2:23–30

    Google Scholar 

  • Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719

    Google Scholar 

  • Smith DF (1984) Stereopsychopharmacology: Past, present and future. Biol Psychiatry 8:327–350

    Google Scholar 

  • Snyder SH, Pasternak GW, Pert CB (1975) Opiate receptor mechanisms. In: Iversen LL, Iversen SD, Snyder SH (eds) Handbook of psychopharmacology, Vol 5. Plenum Press, New York, pp 329–360

    Google Scholar 

  • Thijssen H, Baars L, Drittij-Reijnders J (1985) Stereoselective aspects in the pharmacokinetics and pharmacodynamics of acenocumarol and its amino and acetamide derivatives in the rat. Drug Metab Dispos 13:593–597

    Google Scholar 

  • Thierry A-M, Tassin J-P, Glowinski J (1984) Biochemical and electrophysiological studies of the mesocortical dopamine system. In: Monoamine innervation of cerebral cortex. Liss, New York, pp 233–261

    Google Scholar 

  • Wagner HN, Burns HD, Dannals RF, Wong DF, L»ngström B, Duelfer T, Frost JJ, Raert HT, Links JM, Rosenblom SB, Lukas SE, Kramer AV, Kuhar MJ (1983) Imaging dopamine receptors in the human brain by positron tomography. Science 221:1264–1266

    Google Scholar 

  • Ögren S-O, Hall H, Köhler C, Magnussen O, Sjöstrand S-O (1986) The selective dopamine D2 receptor antagonist raclopride discriminates between dopamine-mediated motor functions. Psychopharmacology 90:287–294

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farde, L., Pauli, S., Hall, H. et al. Stereoselective binding of 11C-raclopride in living human brain — a search for extrastriatal central D2-dopamine receptors by PET. Psychopharmacology 94, 471–478 (1988). https://doi.org/10.1007/BF00212840

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00212840

Key words

Navigation