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 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 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.