TY - JOUR
T1 - Striatal and extrastriatal D 2/D 3-receptor-binding properties of ziprasidone
T2 - A positron emission tomography study with [ 18F]fallypride and [ 11C]raclopride (D 2/D 3-receptor occupancy of ziprasidone)
AU - Vernaleken, Ingo
AU - Fellows, Christine
AU - Janouschek, Hildegard
AU - Bröcheler, Anno
AU - Veselinovic, Tanja
AU - Landvogt, Christian
AU - Boy, Christian
AU - Buchholz, Hans Georg
AU - Spreckelmeyer, Katja
AU - Bartenstein, Peter
AU - Cumming, Paul
AU - Hiemke, Christoph
AU - Rösch, Frank
AU - Schäfer, Wolfgang
AU - Wong, Dean F.
AU - Gründer, Gerhard
PY - 2008/12
Y1 - 2008/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=59049100213&partnerID=8YFLogxK
U2 - 10.1097/JCP.0b013e31818ba2f6
DO - 10.1097/JCP.0b013e31818ba2f6
M3 - Article
C2 - 19011428
AN - SCOPUS:59049100213
SN - 0271-0749
VL - 28
SP - 608
EP - 617
JO - Journal of Clinical Psychopharmacology
JF - Journal of Clinical Psychopharmacology
IS - 6
ER -