Striatal and Extrastriatal D 2 /D 3 -Receptor–Binding Properties of Ziprasidone A Positron Emission Tomography Study With [ 18 F]Fallypride and [ 11 C]Raclopride (D 2 /D 3 -Receptor Occupancy of Ziprasidone) Ingo Vernaleken, MD,* Christine Fellows, MD, y Hildegard Janouschek, MD,* Anno Bro ¨cheler, MD,* Tanja Veselinovic, MD,* Christian Landvogt, MD, z Christian Boy, MD, y Hans-Georg Buchholz, BSc, z Katja Spreckelmeyer,* Peter Bartenstein, MD, x Paul Cumming, PhD, x Christoph Hiemke, PhD, k Frank Ro ¨sch, PhD, { Wolfgang Scha ¨fer, MD, PhD, y Dean F. Wong, MD, PhD, L**yy and Gerhard Gru ¨nder, MD* Abstract: To elucidate the Batypicality[ 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. [ 18 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. D 2 /D 3 -receptor occupancies were expressed relative to binding potentials in 8 unmedicated patients. In a parallel [ 11 C]raclopride-PET study, striatal D 2 /D 3 -receptor occu- pancy was measured in healthy subjects after single oral doses of 40 mg ziprasidone or 7.5 mg haloperidol. Ziprasidone plasma concentrations correlated significantly with D 2 /D 3 -receptor occu- pancies in all volumes of interests. Occupancy in extrastriatal re- gions 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 D 2 /D 3 -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. (J Clin Psychopharmacol 2008;28:608–617) T he second-generation antipsychotic (SGA), ziprasidone, has proven efficacy in the treatment of schizophrenia and mania. 1,2 Ziprasidone combines an antipsychotic efficacy similar to that of the prototypic first-generation antipsychotic (FGA), haloperidol, with the advantages of moderate extra- pyramidal and minimal occurrence of sexual, vegetative, and metabolic side effects. 3,4 Ziprasidone is a D 2 /D 3 dopamine and 5-HT 2 serotonin-receptor antagonist of relatively high affinity. In addition, it is a partial 5-HT 1A –receptor agonist and a serotonin and noradrenaline transporter reuptake in- hibitor. 5,6 Previous positron emission tomography (PET) or single-photon emission computed tomography investigations revealed 60% to 75% striatal D 2 /D 3 -receptor occupancy in patients obtaining clinically effective doses/plasma concen- trations. 7–9 However, the extent of ziprasidone binding to extrastriatal D 2 /D 3 dopamine receptors has not yet been determined. With the advent of high-affinity radiotracers belonging to the class of substituted benzamides, it became possible to quantify extrastriatal dopamine receptors in living human brain. One of the most widely used radiotracers for the quantification of extrastriatal D 2 /D 3 receptors is [ 18 F]fall- ypride ([ 18 F]FP). 10,11 It displays similarly very high affinities for D 2 and D 3 receptors and negligible affinity for any other abundant neuroreceptor. 12 Although earlier PET studies with the moderate-affinity D 2 /D 3 antagonist [ 11 C]raclopride ([ 11 C]RAC) demonstrated that the SGAs clozapine and Original Contribution Journal of Clinical Psychopharmacology  Volume 28, Number 6, December 2008 608 Departments of *Psychiatry and Psychotherapy and yNuclear Medicine, RWTH Aachen University, Aachen; zDepartment of Nuclear Medicine, University of Mainz, Mainz; xDepartment of Nuclear Medicine, Ludwig Maximilian-University, Mu ¨nchen; kDepartment of Psychiatry and {Institute for Nuclear Chemistry, University of Mainz, Mainz, Germany; and Departments of LRadiology, **Psychiatry, and yyNeuroscience, Johns Hopkins Medical Institutions, Baltimore, MD. Received May 19, 2008; accepted after revision August 25, 2008. This work was supported in part by Pfizer, Karlsruhe, Germany (subchronic dosing study) and Pfizer Research, Groton, Connecticut (single-dose study). There was also support by National Institutes of Health grant K24 DA00412 (to Dr Wong). Address correspondence and reprint requests to Ingo Vernaleken, MD, Department of Psychiatry and Psychotherapy, RWTH Aachen Univer- sity, Germany Pauwelsstrasse 30; 52074 Aachen, Germany. E-mail: ivernaleken@ukaachen.de. Copyright * 2008 by Lippincott Williams & Wilkins ISSN: 0271-0749/08/2806-0608 DOI: 10.1097/JCP.0b013e31818ba2f6 Copyright @ 2008 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.