Occupancy of 5-HT1A receptors by clozapine in the primate brain: a PET study.

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Chou YH, Halldin C, Farde L

Occupancy of 5-HT1A receptors by clozapine in the primate brain: a PET study.

Psychopharmacology (Berl). 2003 Mar;166(3):234-40. Epub 2003 Feb 13.

PubMed ID

12589516 [ View in PubMed

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Abstract

RATIONALE: The pharmacological mechanism underlying the atypical properties of the antipsychotic drug clozapine remains to be identified. The serotonin 5-hydroxytryptamine-1A (5-HT(1A)) receptor subtype has been suggested to play a role in the pathophysiology of schizophrenia and is one among several central neuroreceptors for which clozapine has moderate affinity in vitro. OBJECTIVE: The aim of this positron emission tomography (PET) study was to determine 5-HT(1A) receptor occupancy in the monkey brain after IV injection of clozapine in doses that previously have been shown to give plasma concentrations representative of the 200 to 800 mg oral dose range recommended for clinical management of patients. METHODS: Each of four cynomolgus monkeys was examined three times on the same day with PET and the radioligand [carbonyl-(11)C]WAY-100635. The first measurement was performed at baseline conditions, the second after clozapine 1.5 mg/kg and the third after 6 mg/kg. Two additional monkeys were examined at baseline and after 15 mg/kg IV. Central 5-HT(1A) receptor occupancy was calculated using an equilibrium-ratio analysis. RESULTS: The occupancy ranged from 23 to 34% after 1.5 mg/kg clozapine and from 36 to 49% after 6 mg/kg in different brain regions of the four monkeys. The regional receptor occupancy values after 15 mg/kg were between 39 and 51% in the two monkeys. There was no evident difference between the frontal cortex, the temporal cortex and the raphe nucleus. CONCLUSION: The study shows that clozapine occupies 5-HT(1A) receptors in the primate brain at clinically representative plasma concentrations. The results support that the 5-HT(1A) receptor is a candidate target for the atypical drug actions of clozapine.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Clozapine	5-hydroxytryptamine receptor 1A	Protein	Humans	Unknown	Antagonist	Details