Clozapine binds preferentially to cortical D1-like dopamine receptors in the primate brain: a PET study

The D1-like dopamine receptors have been suggested to play a role in the pathophysiology and treatment of schizophrenia. Previous positron emission tomography studies have demonstrated that the atypical antipsychotic clozapine occupies D1-like dopamine receptors in the striatum in clozapine-treated patients.

The aim of the present study was to compare striatal and cortical D1-like dopamine receptor occupancy by clozapine in the primate brain.

Three monkeys were each examined three times at the same day with the radioligand (+)-[11C]NNC 112. The first measurement was at baseline conditions, the second after 1.5 mg/kg and the third after 6 mg/kg clozapine IV. To compare regional levels of nonspecific binding in brain regions, an additional monkey was examined using the inactive enantiomer (-)-[11C]NNC 112. Receptor occupancy was calculated using both the equilibrium-ratio analysis and the simplified reference tissue model.

After 1.5 mg/kg the D1-like dopamine receptor occupancy ranged from 30 to 38% in the striatum, whereas the range was 51 to 57% in the frontal cortex. After 6.0 mg/kg the occupancy was 53 to 64% in the striatum and 63 to 83% in the frontal cortex. The differences between striatal and cortical D(1)-like receptors occupancy were between 12 and 25%. The study with (-)-[11C]NNC 112 did not show regional differences in nonspecific binding that might explain the regional differences in occupancy.

The higher D1-like dopamine receptor occupancy in the frontal cortex may reflect a different distribution of the D1 and D5 dopamine receptor subtypes among brain regions and different affinity of clozapine for the two subtypes. The finding supports the suggestion that binding to D1-like dopamine receptors may explain clozapine's atypical drug actions.