title: Striatal and extrastriatal D2/D3-receptor-binding properties of ziprasidone: a positron emission tomography study with [18F]Fallypride and [11C]raclopride (D2/D3-receptor occupancy of ziprasidone).
abstract: To elucidate the "atypicality" of ziprasidone, its striatal and extrastriatal D2/D3-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 D2/D3-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. D2/D3-receptor occupancy is rapidly attuning to the daily course of ziprasidone plasma levels, suggesting relatively high intraday variations of D2/D3-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.
authors.affiliation: Department of Psychiatry and Psychotherapy, RWTH Aachen University, Aachen, Germany. ivernaleken@ukaachen.de
authors.forename: Ingo
authors.initials: I
authors.lastname: Vernaleken
authors.forename: Christine
authors.initials: C
authors.lastname: Fellows
authors.forename: Hildegard
authors.initials: H
authors.lastname: Janouschek
authors.forename: Anno
authors.initials: A
authors.lastname: Bröcheler
authors.forename: Tanja
authors.initials: T
authors.lastname: Veselinovic
authors.forename: Christian
authors.initials: C
authors.lastname: Landvogt
authors.forename: Christian
authors.initials: C
authors.lastname: Boy
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Buchholz
authors.forename: Katja
authors.initials: K
authors.lastname: Spreckelmeyer
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
authors.forename: Christoph
authors.initials: C
authors.lastname: Hiemke
authors.forename: Frank
authors.initials: F
authors.lastname: Rösch
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schäfer
authors.forename: Dean F
authors.initials: DF
authors.lastname: Wong
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D001479:Basal Ganglia / Q000000981:diagnostic imaging / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000378:metabolism; D020891:Raclopride / Q000378:metabolism; D019275:Radiopharmaceuticals / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D001549:Benzamides; D002250:Carbon Radioisotopes; C493593:DRD3 protein, human; D018492:Dopamine Antagonists; D005462:Fluorine Radioisotopes; C094948:N-((1-allyl-2-pyrrolidinyl)methyl)-5-(3-fluoropropyl)-2,3-dimethoxybenzamide; D010879:Piperazines; D011759:Pyrrolidines; D019275:Radiopharmaceuticals; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; D020891:Raclopride; C092292:ziprasidone