BACKGROUND Perospirone is a novel second-generation antipsychotic drug with high affinity to dopamine D(2) receptor and short half-life of plasma concentration. There has been no investigation of dopamine D(2) receptor occupancy in patients with schizophrenia and the time course of occupancy by antipsychotics with perospirone-like properties. OBJECTIVE We investigated dopamine D(2) receptor occupancy by perospirone in patients with schizophrenia and the time course of occupancy in healthy subjects. METHODS Six patients with schizophrenia taking 16-48 mg/day of perospirone participated. Positron emission tomography (PET) scans using [(11)C]FLB457 were performed on each subject, and dopamine D(2) receptor occupancies were calculated. Moreover, baseline and three serial PET using [(11)C]raclopride were performed at 1.5, 8, and 25.5 h after administration of a single dose of 16 mg of perospirone on four healthy male subjects, and occupancy was calculated for each scan. RESULTS Dopamine D(2) receptor occupancy in the temporal cortex of patients ranged from 39.6% to 83.8%. Especially, occupancy in two patients who took 16 mg of perospirone 2.5 h before PET was over 70%. Mean occupancy in the striatum of healthy subjects was 74.8% at 1.5 h, 60.1% at 8 h, and 31.9% at 25.5 h after administration. CONCLUSIONS Sixteen milligrams of perospirone caused over 70% dopamine D(2) receptor occupancy near its peak level, and then occupancy dropped to about half after 22 h. The time courses of receptor occupancy and plasma concentration were quite different. This single dosage may be sufficient for the treatment of schizophrenia and might be useful as a new dosing schedule choice.