Therapeutic monitoring of new atypical antipsychotics shown for the dopamine receptor antagonist ziprasidone: A [18F]fallypride PET study in patients with schizophrenia

Abstract

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Objectives: The use of new high-affinity PET ligands for D2/D3 dopamine receptors, such as [18F]fallypride (FP), allows for quantification of both striatal and extrastriatal binding of antipsychotics in a single PET-scan. We present occupancy (OCC) data for the second-generation antipsychotic, ziprasidone, which further elucidates its clinical characteristics. Methods: The study involved 23 patients diagnosed with schizophrenia (DSM-IV). 15 were treated with ziprasidone according to clinical needs, while the other 8 were unmedicated and acted as age-matched controls. All subjects underwent dynamic PET-Scans over 180 minutes after bolus injection of FP. Time-activity curves were generated for several striatal and extrastriatal regions. Binding potentials (BP) were calculated by means of the simplified reference tissue model. OCC was calculated as percent reduction in BP of treated patients relative to controls. Integrated plasma concentrations and OCC were fitted to a simple one-site ligand binding model according to the law of mass-action using nonlinear regression. Results: A marked OCC of D2/D3 receptors by ziprasidone was shown in striatal and extrastriatal regions, with the highest values in thalamus (mean ± SD 58±19%, range 11-83%), caudate nucleus (57±20%, range 18-83%), putamen (54±20%, range 12-83%) and inferior temporal cortex (56±13%, range 29-72%). When Emax was constrained to 100%, plasma concentrations (range 27-288 ng/ml) were strongly correlated to regional OCC in the putamen (EC50 65 ng/ml, p=0.01), caudate nucleus (EC50 59 ng/ml, p<0.01) and inferior temporal cortex (EC50 42 ng/ml, p<0.01). Conclusions: EC50 of striatal and extrastriatal regions differed considerably, indicating a preferential extrastriatal binding at low plasma levels, which is lost at higher plasma concentrations. This might be an important mechanism in explaining the concentration-dependent “atypical” action of ziprasidone.

Research Support (if any): This study was supported by Pfizer. C. Fellows was supported by a grant from the German Research Council (DFG), KFO 112, 2-1 and 2-2.