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

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.

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.

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.

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.

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.