RATIONALE: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D(2) receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited. OBJECTIVES: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D(2) receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. METHODS: PET examination with [(11)C]raclopride was performed to measure the dopamine D(2) receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [(11)C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. RESULTS: Dopamine D(2) receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. CONCLUSIONS: Clozapine could occupy a high proportion of dopamine D(2) receptors. The time course of occupancy was relatively fast, with a half-life of several hours.
RATIONALE: Clozapine is a unique antipsychotic with very low propensity to cause motor side effects. In contrast to most other antipsychotics that block more than 70% of dopamine D(2) receptors at therapeutic doses, clozapine occupies less than 70%. Furthermore, even at maximum occupancy, 70% is not exceeded. Several mechanisms have been proposed as explanations for this low D(2) receptor occupancy, but clear evidence is limited. OBJECTIVES: In patient studies the data are limited by the dose-range that can be safely used; therefore, the aims of this study were to examine the maximum occupancy of dopamine D(2) receptors with up to 5.0 mg/kg of bolus injection of clozapine to non-human primates and to measure the time course of occupancy. METHODS: PET examination with [(11)C]raclopride was performed to measure the dopamine D(2) receptor occupancy in the striatum of two monkeys after the bolus injection of 0.2-5.0 mg/kg clozapine. [(11)C]raclopride was injected sequentially to follow the time course of occupancy up to 7 h after the clozapine injection. RESULTS:Dopamine D(2) receptor occupancy reached up to 83% after 5.0 mg/kg clozapine injection. Occupancy decreased with a half-life of 7.22 h after 5.0 mg/kg clozapine and 5.25 h after 1.0 and 2.0 mg/kg clozapine. CONCLUSIONS:Clozapine could occupy a high proportion of dopamine D(2) receptors. The time course of occupancy was relatively fast, with a half-life of several hours.
Authors: Georges Vauquelin; Sophie Bostoen; Patrick Vanderheyden; Philip Seeman Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2012-02-14 Impact factor: 3.000