Determination of dopamine D 2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjec
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ORIGINAL INVESTIGATION
Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects Dean F. Wong & Hiroto Kuwabara & James Robert Brašić & Thomas Stock & Atul Maini & Emily G. Gean & Antony Loebel
Received: 13 September 2012 / Accepted: 29 March 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Rationale A positron emission tomography (PET) study of dopamine D2 receptor occupancy was conducted to support a rational dose selection for clinical efficacy studies with lurasidone, an atypical antipsychotic that was approved for the treatment of schizophrenia by the FDA in late 2010. Objectives To determine the dopamine D2 receptor occupancy of lurasidone in the ventral striatum, putamen and caudate nucleus, and to characterize the relationship between lurasidone serum concentration and D2 receptor occupancy. Methods A single oral dose of lurasidone (10, 20, 40, 60, or 80 mg) was administered sequentially to healthy male subjects (n=4 in each cohort). Two PET scans were performed. For each scan, 20 mCi of [11C]raclopride was administered intravenously as a bolus injection, followed immediately by 90 min of PET scan acquisitions. Results The D2 receptor occupancy levels were 41–43 % for 10 mg, 51–55 % for 20 mg, 63–67 % for 40 mg, 77–84 % for 60 mg, and 73–79 % for 80 mg of lurasidone. The relationship between D 2 receptor occupancy and the mean serum D. F. Wong (*) : H. Kuwabara : J. R. Brašić : A. Maini : E. G. Gean Department of Radiology, Johns Hopkins Medical Institutions (JHMI), 601 North Caroline Street, Room JHOC 3245, Baltimore, MD 21287-0807, USA e-mail: [email protected] T. Stock PAREXEL International, Harbor Hospital Center, Baltimore, MD, USA A. Loebel Sunovion Pharmaceuticals Inc, Fort Lee, NJ, USA A. Loebel Sunovion Pharmaceuticals Inc, Marlborough, MA, USA
lurasidone concentration during the PET scan (CPET) was similar for the putamen, caudate nucleus, and ventral striatum regions. Mean D2 receptor occupancy levels correlated well with average peak serum concentration of lurasidone. Conclusions In healthy volunteers, single doses of lurasidone 40–80 mg resulted in D2 receptor occupancy levels of >60 %, a level of receptor occupancy previously associated with clinical response for atypical antipsychotics. Keywords Positron emission tomography . Antipsychotic agents . Dopamine D2 receptors . Lurasidone . Dose–response relationship . Drug
Introduction Lurasidone is a benzisothiazol derivative with high affinity for dopamine D2, serotonin 5-HT7, 5-HT2A, and 5-HT1A receptors (Ishibashi et al. 2010). Lurasidone is D2 selective, with a 16-fold greater affinity for D2 compared with D3 receptors (Ishibashi et al. 2010). The antipsychotic efficacy of lurasidone has been demonstrated in multiple double-blind, placebo-controlled studies with significant improvement in psychotic symptoms during short-term treatment, and sustained improvement during long-term treatment (Nakamura et al. 2009; Meltzer et al. 2011; Citrome et al. 2011; Loebel et al. 2013b
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