Determination of dopamine D2 receptor occupancy by lurasidone using positron emission tomography in healthy male subjects

Rationale A positron emission tomography (PET) study of dopamine D-2 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 D-2 receptor occupancy of lurasidone in the ventral striatum, putamen and caudate nucleus, and to characterize the relationship between lurasidone serum concentration and D-2 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 [C-11]raclopride was administered intravenously as a bolus injection, followed immediately by 90 min of PET scan acquisitions. Results The D-2 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 lurasidone concentration during the PET scan (CPET) was similar for the putamen, caudate nucleus, and ventral striatum regions. Mean D-2 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 D-2 receptor occupancy levels of >60 %, a level of receptor occupancy previously associated with clinical response for atypical antipsychotics.