To evaluate the striatal D3/D2 receptor occupancy of cariprazine (RGH-188) in healthy volunteers and schizophrenic patients, and assess the correlation between cariprazine plasma concentration and receptor occupancy.

Single- (0.5 mg) or multiple-dose (1 mg/day, 14 days) cariprazine was administered to healthy adult males (N=5) in an open-label positron emission tomography (PET) study. In a separate open-label PET study, multiple-dose cariprazine (0.5-3.0 mg/day, 14 days) was administered to adult male schizophrenic patients (N=8). Healthy volunteers had 1 predose and 1 postdose raclopride PET scan; schizophrenic patients had 1 predose and up to 3 postdose fallypride scans. Cariprazine plasma concentrations were determined by LC-MS/MS.

In healthy volunteers, single-dose cariprazine 0.5 mg resulted in low plasma concentration (0.1 ng/ml) and was associated with 12% maximum D3/D2 receptor occupancy; cariprazine 1 mg/day for 14 days resulted in cariprazine plasma concentrations of 2.3-3.4 ng/ml and >70% D3/D2 receptor occupancy. In schizophrenic patients, cariprazine 1.5 mg/day for 14 days resulted in cariprazine plasma concentrations of 2.5-3.4 ng/ml and >70% receptor occupancy; cariprazine 3.0 mg/day resulted in ≥90% occupancy. Predicted Emax values in schizophrenic patients approached 100% D3/D2 occupancy for dorsal and ventral striatum.

D3/D2 receptor occupancy in dorsal and ventral striatum was similar for cariprazine 1.0 mg/day in healthy volunteers and cariprazine 1.5 mg/day in schizophrenic patients. In both, higher receptor occupancy was associated with higher cariprazine plasma concentration. Cariprazine at 1.5 to 3.0 mg/day showed D3/D2 receptor occupancy within the predicted effective antipsychotic range.