Striatal and extrastriatal D2/3-receptor binding of ziprasidone: Implications of different study schedules

Abstract

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Objectives: The striatal and extrastriatal D2/3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy results after single-dose ziprasidone ingestion in healthy controls.

Methods: 18F-Fallypride PET was performed in 15 patients under steady-state ziprasidone treatment 4.75-33.50 h after last ingestion. Binding potentials (BP) were calculated for striatal and extrastriatal regions. Receptor occupancy was expressed relative to BP in untreated patients. In a parallel 11C-raclopride PET study, striatal D2/3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol.

Results: Ziprasidone plasma concentrations correlated highly with D2/3-receptor occupancies in all VOIs. Receptor binding was about 10% higher in extrastriatal than in striatal regions. EC50 values were higher in striatal regions (temporal cortex: 39 ng/ml; putamen: 64 ng/ml), irrespective of the time between last dosing and scan. Single ziprasidone doses resulted in higher occupancies exceeding the 95% prediction limits of the occupancy vs. plasma concentrations for chronic dosing.

Conclusions: Ziprasidone shares moderate preferential extrastriatal D2/3-receptor binding with some other atypicals. This relationship is independent of the time after the last ingestion. Furthermore, single-dose studies demonstrate significantly higher D2/3 occupancies at clinically ineffective doses. The factors that may predict similar discrepancies are important for the future design of single versus multiple dose PET occupancy studies of novel antipsychotics.

Research Support: Pfizer; NIH K24 DA00412