Striatal and extrastriatal D 2/D 3-receptor-binding properties of ziprasidone: A positron emission tomography study with [ 18F]fallypride and [ 11C]raclopride (D 2/D 3-receptor occupancy of ziprasidone)

Ingo Vernaleken, Christine Fellows, Hildegard Janouschek, Anno Bröcheler, Tanja Veselinovic, Christian Landvogt, Christian Boy, Hans Georg Buchholz, Katja Spreckelmeyer, Peter Bartenstein, Paul Cumming, Christoph Hiemke, Frank Rösch, Wolfgang Schäfer, Dean F. Wong, Gerhard Gründer

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Abstract

To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D 2/D 3-receptor binding was characterized in patients with schizophrenia under steady-state conditions. These data were compared with striatal receptor occupancy values after single-dose ziprasidone ingestion in healthy controls. [F]fallypride positron emission tomography (PET) recordings were obtained in 15 patients under steady-state ziprasidone treatment at varying time points after the last dose. Binding potentials were calculated for striatal and extrastriatal regions. D2/D3-receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [C]raclopride-PET study, striatal D 2/D 3-receptor occupancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D2/D3-receptor occupancies in all volumes of interests. Occupancy in extrastriatal regions was approximately 10% higher than in striatal regions. Half maximal effective concentration values were consistently higher in striatal than in extrastriatal 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 versus plasma concentrations for chronic dosing. Ziprasidone shares moderate preferential extrastriatal D2/D3-receptor binding with some other atypicals. D 2/D 3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D 2/D 3-receptor binding. The discrepancies between single-dose and steady-state results are important for the future design of dose-finding PET occupancy studies of novel antipsychotics. Single-dose studies may not be totally relied on for final dose selection.

Original languageEnglish (US)
Pages (from-to)608-617
Number of pages10
JournalJournal of clinical psychopharmacology
Volume28
Issue number6
DOIs
StatePublished - Dec 1 2008

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ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

Vernaleken, I., Fellows, C., Janouschek, H., Bröcheler, A., Veselinovic, T., Landvogt, C., Boy, C., Buchholz, H. G., Spreckelmeyer, K., Bartenstein, P., Cumming, P., Hiemke, C., Rösch, F., Schäfer, W., Wong, D. F., & Gründer, G. (2008). Striatal and extrastriatal D 2/D 3-receptor-binding properties of ziprasidone: A positron emission tomography study with [ 18F]fallypride and [ 11C]raclopride (D 2/D 3-receptor occupancy of ziprasidone). Journal of clinical psychopharmacology, 28(6), 608-617. https://doi.org/10.1097/JCP.0b013e31818ba2f6