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Psychopharmacology

, Volume 113, Issue 2, pp 149–156 | Cite as

PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor

  • Per Karlsson
  • Lars Farde
  • Christer Halldin
  • Carl-Gunnar Swahn
  • Göran Sedvall
  • Christian Foged
  • Kristian Tage Hansen
  • Birte Skrumsager
Original Investigations

Abstract

The benzazepines NNC 687 and NNC 756 have in animal studies been described as selective D1-dopamine receptor antagonists. Both compounds have been labeled with11C for examination by positron emission tomography (PET). In the present study central receptor binding was studied in monkeys and healthy men. After IV injection of both radioligands in Cynomolgus monkeys radioactivity accumulated markedly in the striatum, a region with a high density of D1-dopamine receptors. This striatal uptake was displaced by high doses of the selective D1-antagonist SCH 23390 (2 mg/kg) but not by the 5HT2-antagonist ketanserin (1.5 mg/kg) or the selective D2-antagonist raclopride (3 mg/kg). The cortical uptake after injection of [11C]NNC 687 was not reduced in displacement experiments with ketanserin. The cortical uptake of [11C]NNC 756 was reduced in displacement and protection experiments with ketanserin by 24–28% (1.5 mg/kg), whereas no reduction could be demonstrated on striatal uptake. In healthy males both compounds accumulated markedly in the striatum. For [11C]NNC 687 the ratio of radioactivity in the putamen to cerebellum was about 1.5. For [11C]NNC 756 the ratio was about 5. This ratio of 5 for [11C]NNC 756 is the highest obtained so far for PET radioligands for the D1-dopamine receptor.

Key words

Positron emission tomography D1-dopamine receptors NNC 687 NNC 756 Cynomolgus monkey Human 
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References

  1. Andersen PH, Grønvald FC, Hohlweg R, Hansen LB, Guddal E, Braestrup C, Nielsen EB (1992) NNC-112, NNC-687 and NNC-756, new selective and highly potent dopamine D1 receptor antagonists. Eur J Pharmacol 219:45–52Google Scholar
  2. Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, Caillard V, Blin J, Huret JD, Loc'h C, Maziere B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 99:463–472Google Scholar
  3. Bergström M, Boëthius J, Eriksson L, Greitz T, Ribbe T, Widén L (1981) Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 5:136–141Google Scholar
  4. Blin J, Pappata S, Kiyosawa M, Crouzel C, Baron JC (1988) [18F]Setoperone: a new high-afinity ligand for positron emission tomography study of the serotonin-2 receptors in baboon brain in vivo. Eur J Pharmacol 147:73–82Google Scholar
  5. Bunzov JR, Van Tol HHM, Grandy DK, Albert P, Salon J, Christie M, Machida CA, Neve KA, Civelli O (1988) Cloning and expression of a rat D2 dopamine receptor. Nature 336:783–787Google Scholar
  6. Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144Google Scholar
  7. Christensen AV, Arnt J, Hyttel J, Larsen J-J, Svendsen O (1984) Pharmacological effects of a specific dopamine D-1 antagonist SCH 23390 in comparison with neuroleptics. Life Sci 34:1529–1540Google Scholar
  8. Cortés R, Camps M, Gueye B, Probst A, Palacios JM (1989) Dopamine receptors in human brain: autoradiographic distribution of D1 and D2 sites in Parkinson syndrome of different etiology. Brain Res 483:30–38Google Scholar
  9. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483Google Scholar
  10. Dearry A, Gingrich JA, Falardeau P, Freemeau Jr RT, Bates MT, Caron MG (1990) Molecular cloning and expression of the gene for a human D1 dopamine receptor. Nature 347:72–76Google Scholar
  11. Farde L, Halldin C, Stone-Elander S, Sedvall G (1987) PET analysis of human dopamine receptor subtypes using11C-SCH 23390 and11C-raclopride. Psychopharmacology 92:278–284Google Scholar
  12. Farde L, Wiesel F-A, Halldin C, Sedvall G (1988) Central D2-dopamine occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76Google Scholar
  13. Farde L (1992a) Selective D1- and D2-dopamine receptor blockade both induce akathisia in humans — a PET study with [11C]SCH 23390 and [11C]raclopride. Psychopharmacology 107:23–29Google Scholar
  14. Farde L, Nordström A-L, Wiesel F-A, Pauli S, Halldin C, Sedvall G (1992b) PET-analysis of central D1- and D2-dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine — relation to extrapyramidal side effects. Arch Gen Psychiatry 49:538–544Google Scholar
  15. Hall H, Farde L, Sedvall G (1988) Human dopamine receptor subtypes — in vitro binding analysis using3H-SCH 23390 and3H-raclopride. J Neural Transm 73:7–21Google Scholar
  16. Halldin C, Hansen K, Foged C, Grønvald FC, Farde L (1991a) Preparation of [11C]NNC 756, a new selective dopamine D1 receptor ligand for PET. J Nucl Med 32:934–935Google Scholar
  17. Halldin C, Swahn C-G, Farde L, Litton J-E, Sedvall G (1991b) Determination of [11C]SCH 23390 and its radioactive metabolites in plasma by HPLC. Eur J Nucl Med 18:526Google Scholar
  18. Halldin C, Foged C, Farde L, Karlsson P, Hansen K, Grønvald F, Swahn C-G, Hall H, Sedvall G (1993) [11C]NNC 687 and [11C]NNC 756, dopamine D-1 receptor ligands. Preparation, autoradiography and PET investigation in monkey. Nucl Med Biol (in press)Google Scholar
  19. Hyttel J (1983) SCH23390 — the first selective dopamine D1-antagonist. Eur J Pharmacol 91:53–154Google Scholar
  20. Iorio L (1981) A benzazepine with atypical effects on dopaminergic systems. Pharmacologist 23:136Google Scholar
  21. Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharmacol Exp Ther 226:462–468Google Scholar
  22. Kebabian JW, Calne DB (1979) Multiple receptors for dopamine. Nature 277:93–96Google Scholar
  23. Litton JE, Holte S, Eriksson L (1990) Evaluation of the Karolinska new positron camera system; the Scanditronix PC2048-15B. IEEE Trans Nucl Sci 37:743–748Google Scholar
  24. McQuade RD, Duffy RA, Coffin VL, Barnett A (1992) In vivo binding to dopamine receptors: a correlate of potential antipsychotic activity. Eur J Pharmacol 215:29–34Google Scholar
  25. Meador-Woodruff JH, Mansour A, Healy DJ, Kuehn R, Zhou Q-Y, Bunzow JR, Akil H, Civelli O, Watson Jr SJ (1991) Comparison of the Distributions of D1 and D2 dopamine receptor mRNAs in rat brain. Neuropsychopharmacology 5:231–242Google Scholar
  26. Nielsen EB, Andersen PH (1992) Dopamine receptor occupancy in vivo: behavioral correlates using NNC-112, NNC-687 and NNC-756, new selective dopamine D1 receptor antagonists. Eur J Pharmacol 219:35–44Google Scholar
  27. Pazos A, Probst A, Palacios JM (1987) Serotonin receptors in the human brain — IV autoradiographic mapping of serotonin-2 receptors. Neuroscience 21:123–139Google Scholar
  28. Sedvall G, Farde L, Barnett A, Hall H, Halldin C (1991)11C-SCH 39166, a selective ligand for visualization of dopamine-D1 receptor binding in the monkey brain using PET. Psychopharmacology 103:150–153Google Scholar
  29. Smith M, Wolf AP, Brodie JD, Arnett CD, Barouche F, Shiue C-Y, Fowler JS, Russell JAG, MacGregor RR, Wolkin A, Angrist B, Rotrosen J, Peselow E (1988) Serial [18F]N-methylspiroperidol PET studies to measure changes in antipsychotic drug D-2 receptor occupancy in schizophrenic patients. Biol Psychiatry 23:653–663Google Scholar
  30. Sokoloff P, Giros B, Martres M-P, Bouthenet M-L, Schwartz J-C (1990) Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature 357:146–151Google Scholar
  31. Sunahara RK, Guan H-C, O'Dowd BF, Seeman P, Laurier JG, Ng G, George SR, Torchia J, van Tol HHM, Niznik HB (1991) Cloning of the gene for a human dopamine D5 receptor with higher affinity for dopamine than D1. Nature 350:614–619Google Scholar
  32. Swahn C-G, Farde L, Halldin C, Sedvall G (1992) Ligand metabolites in plasma during PET studies with the11C-labelled dopamine antagonists, raclopride, SCH 23390 and N-methylspiroperidol. Hum Psychopharmacol 7:97–103Google Scholar
  33. van Rossum JM (1966) The significance of dopamine receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther 160:492–494Google Scholar
  34. Van Tol HHM, Bunzow JR, Guan H-C, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614Google Scholar
  35. Waddington J, O'Boyle K (1989) Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D1-antagonists. Pharmacol Ther 43:1–52Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Per Karlsson
    • 1
  • Lars Farde
    • 1
  • Christer Halldin
    • 1
  • Carl-Gunnar Swahn
    • 1
  • Göran Sedvall
    • 1
  • Christian Foged
    • 2
  • Kristian Tage Hansen
    • 2
  • Birte Skrumsager
    • 2
  1. 1.Department of Psychiatry and PsychologyKarolinska InstitutetStockholmSweden
  2. 2.Novo Nordisk A/SMåløvDenmark

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