Abstract
The binding of 11C-labelled clozapine in the brain was studied in three drug-free schizophrenic patients and in three healthy volunteers. High radioactivities were found in the striatum and in the frontal cortex. The rate constantk 3, which is proportional to receptor association rate and the number of receptors, was lower in the frontal cortex compared to the striatum. No obvious difference between the two brain areas was seen for the dissociation rate constant from the receptors (k 4). Two schizophrenic patients were reexamined after pretreatment with haloperidol, one after 6 weeks of treatment with a low oral dose, the other one after an IV injection 1 h before 11C-clozapine was given. After haloperidol pretreatment, the binding of 11C-clozapine in striatum and frontal cortex was reduced, more pronounced in the striatum, indicating competition for D-2 dopamine binding sites. Our finding indicates that clozapine has an affinity for a receptor population in the frontal cortex that is predominantly not of the dopamine-D2 type. This feature might be of importance for the unique clinical profile of the drug.
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Andén N-E, Stock G (1973) Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system. J Pharm Pharmacol 25:346–348
Andersen PH (1988) Comparison of the pharmacological characteristics of3H-SCH23390 binding to dopamine receptors in vivo in mouse brain. Eur J Pharmacol 146:113–120
Andersson PH, Braestrup C (1986) Evidence for different states of the dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylateacyclase-coupled state of the D1 receptor. J Neurochem 47:1822–1831
Andreasen N, Nasrallah H, Dunn V, Olsson S, Grove W, Ehrhardt J, Coffman J, Crossett J (1986) Structural abnormalities in the frontal system in schizophrenia. A magnetic resonance imaging study. Arch Gen Psychiatry 43:136–144
Angst J (1971) Ergebnisse eines Doppelblindversuches von HF 1854 (8-chlor-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4) diazepin im Vergleich zu Levomepromazin. Pharmacopsychiatry 4:192–200
Bondesson U, Lindström LH (1988) Analysis of clozapine and its N-dealkylated metabolite in plasma by use of gas chromatography-mass spectrometry with single ion detection. Psychopharmacology 95:472–475
Bürki HR, Eichenberger E, Sayers AC (1975) Clozapine and the dopamine hypothesis in schizophrenia, a critical appraisal. Pharmacopsychiat. Neuropsychopharmacology 8:115–121
Cheng YF, Lundberg T, Bondesson U, Lindström LH, Gabrielsson J (1988) Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol 34:445–449
Chipkin RE, Latranyi MB (1987) Similarity of clozapine and SCH 23390 in reserpinized rats suggests a common mechanism of action. Eur J Pharmacol 136:371–375
Eckernâs S-Å, Aquilonius SM, Hartvig P, Långström B (1987) Positron emission tomography (PET) in the study of dopamine receptors in the primate brain: evaluation of a kinetic model using 11C-N-methylspiperone. Acta Neurol Scand 75:168–178
Ekblom B, Hâggström J-E (1974) Clozapine (Leponex) compared with chlorpromazine: a double-blind evaluation of pharmacological and clinical properties. Curr Ther Res 16:945–957
Eriksson L, Bohm C, Kesselberg M, Blomquist G, Litton J, Widen L, Bergström M, Eriksson K, Greitz T (1982) A four ring positron camera system for emission tomography of the brain. IEEE Trans Nucl Sci 29:539–543
Farde L, Ehrin E, Eriksson L, Greitz T, Hall H, Hedström C-G, Litton J-E, Sedval 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
Farde L, Halldin C, Stone-Elander S, Sedvall G (1987) PET analysis of human dopamine receptor subtypes using 11C-SCH23390 and 11C-raclopride. Psychopharmacology 92:278–284
Farde L, Pauli S, Hall H, Eriksson L, Halldin C, Högberg T, Nilsson L, Sjögren I, Stone-Elander S (1988a) Stereoselective binding of 11C-raclopride in living human brain — a search for extrastriatal central D2-dopamine receptors by PET. Psychopharmacology 94:471–478
Farde L, Wiesel F-A, Halldin C, Sedvall G (1988b) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–75
Fog R (1972) On stereotypy and catalepsy: studies of the effects of amphetamines and neuroleptics in rats (thesis). Acta Neurol Scand [Suppl] 50:1–66
Gerlach J, Koppelhus P, Helweg E, Monrad A (1974) Clozapine and haloperidol in a single-blind cross-over trial: therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand 50:410–424
Hall H, Farde L, Sedvall G (1988) Human dopamine receptor subtypes — in vitro binding analysis using3H-raclopride. J Neural Transm 73:7–21
Hartvig P, Eckernâs S-A, Lindström LH, Ekblom B, Bondesson U, Lundquist H, Halldin C, Någren K, Långström B (1986) Receptor binding of N-(methyl-11C)clozapine in the brain of rhesus monkey studied by positron emission tomography (PET). Psychopharmacology 89:248–252
Hartvig P, Eckernâs S-A, Ekblom B, Lindström LH, Lundqvist H, Axelsson S, Fasth KJ, Gullberg P, Långström B (1988) Receptor binding and selectivity of three 11C-labelled dopamine receptor antagonists in the brain of rhesus monkeys studied with positron emission tomography. Acta Neurol Scand 77:314–321
Hyttel J (1974) Effect of neuroleptics on the disappearance rate of 11C-labelled catecholamines formed from 11C-tyrosine in mouse brain. J Pharm Pharmacol 26:588–596
Kebabian JW, Agui T, Oene JC van, Shigematsu K, Saavedra JM (1986) The D1 dopamine receptor: new perspectives. TIPS March 99-99
Lundqvist H (1986) Determination of receptor kinetic parameters by use of a receptor-free reference tissue. Medical application of cyclotrons IV. Ann Univ Tukuensis D:27, 1988
Långström B, Antoni G, Halldin C, Svârd H, Bergson G (1982) Synthesis of some 11C-labelled alkaloids. Chem Scrip 20:46–48
Långström B, Antoni G, Halldin C (1984) 11C-methyl-iodide in N-alkylation reactions of C11-labelled radiopharmaceuticals. J Label Comp Radiopharmaceut 21:1200–1202
Maziérè B, Loch C, Baron J-C, Sgouropoulos P, Duqnesnoy ND, Antona R, Cambon H (1985) In vivo quantitative imaging of dopamine receptors in human brain using positron emission tomography and (76Br)bromospiperone. Eur J Pharmacol 114:276–282
Muller HF (1985) Prefrontal cortex dysfunction as a common factor in psychosis. Acta Psychiatr Scand 71:431–440
Peroutka SJ, Snyder SH (1980) Relationship of neuroleptic drug effects at brain dopamine, serotonin, adrenergic and histamine receptors to clinical potency. Am J Psychiatry 137:1518–1522
Sawyers A, Burki H, Ruch W, Asper H (1975) Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesia. Effects of clozapine, haloperidol, loxapine and chlorpromazine. Psychopharmacologia 41:97–104
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
Seeman P, Lee T, Chaou-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719
Seeman P, Grigoriadis D (1987) Dopamine receptors in brain and periphery. Neurochem Int 10:1–25
Simpson GM, Varga E (1974) Clozapine — a new antipsychotic agent. Curr Ther Res 16:679–686
Stille G, Lauener H, Eichenberg E (1971) The pharmacology of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine) (clozapine). Il Farmaco 26:603–625
Wagner H, Burns D, Dannals R, Wong DF, Långström B, Dvelfer T, Frost II, Ravert HT, Links IM, Rosenbloom SB, Lukas SE, Kranzr AV, Kuhar MJ (1983) Imaging dopamine receptors in the human brain by positron tomography. Science 221:1264–1266
Wong DF, Wagner HN, Dannals R, Links J, Frost J, Ravert H, Wilson A, Rosenbaum A, Gjedde A, Douglass K, Petronis J, Felstein M, Toung T, Burns D, Kuhar M (1984) Effects of age on dopamine and serotonin receptors measured by positron tomography in the living human brain. Science 226:1393–1396
Worley PF, Baraban JM, De Souza EB, Snyder SH (1986) Mapping second messenger systems in the brain: differential localizations of adenylate cyclase and protein kinase C. Proc Natl Acad Sci USA 83:4053–4057
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Lundberg, T., Lindström, L.H., Hartvig, P. et al. Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug-free schizophrenics and healthy volunteers. Psychopharmacology 99, 8–12 (1989). https://doi.org/10.1007/BF00634444
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DOI: https://doi.org/10.1007/BF00634444