The temporal and extrastriatal D2/D3 receptor binding profile of aripiprazole in patients with schizophrenia

Abstract

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Objectives: It has been previously shown that the partial dopamine (DA) receptor agonist antipsychotic, aripiprazole (ARI), occupies more than 90% of striatal D2 receptors at clinically effective doses. In order to further characterize ARI’s extrastriatal and temporal binding characteristics, we performed [18F]fallypride (FP) PET studies in patients with schizophrenia at varying time points after the last dosing. Methods: D2-like DA receptors were quantified with FP-PET in 19 patients suffering from schizophrenia (DSM-IV). 11 were treated with ARI, 8 age-matched drug-free patients served as control group. After varying time points after the last drug administration (range 5-78 h), subjects underwent dynamic PET scans over 180 minutes. Binding potentials (BP) were calculated by means of the simplified reference tissue model. Occupancy (OCC) was calculated as percent reduction in BP of treated patients relative to controls. Plasma concentrations and percent binding data were fit to a simple one-site ligand binding model by nonlinear regression. Results: D2/D3 receptor OCC was high in all brain regions (mean±SD, putamen 82±13%, caudate 83±12%, thalamus 83±8%, inferior temporal cortex 82±10%), with no difference between striatal and extrastriatal regions. D2/D3 receptor OCC was still above 80% in a patient who had received his last dose 78 h prior to the PET scan. Nonlinear regression analysis revealed Emax (maximum attainable receptor OCC) values close to saturation in all brain regions. EC50 (plasma concentration predicted to provide 50% of the maximum attainable OCC) values were between 8 ng/ml in cortex and 14 ng/ml in putamen. Conclusions: ARI due to its high affinity to D2/D3 receptors and its long half-life of about 72 hours at clinical doses occupies very high amounts of its target receptor homogenously throughout the brain; dissociation from those receptors is very slow. It can be calculated from our results that in patients with plasma concentrations above approximately 400 ng/ml D2/D3 receptors are still almost saturated for nearly one week after the last dose.

Research Support (if any): Bristol-Myers Squibb