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 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 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 D₂ receptor occupancy and the mean serum lurasidone concentration during the PET scan (C _PET) 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.