A positron emission tomography occupancy study of brexpiprazole at dopamine D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors, and serotonin reuptake transporters in subjects with schizophrenia

The objective of this study (NCT01854944) was to assess D₂/D₃, 5-HT_1A, 5-HT_2A and serotonin transporter (SERT) occupancies of brexpiprazole in adult subjects with schizophrenia in order to identify the in vivo pharmacologic profile that may be relevant to the antipsychotic, antidepressant, and side effect profiles of the drug. Subjects were grouped into three independent cohorts of four subjects each. All subjects underwent positron emission tomography (PET) scans with two different radiotracers at baseline prior to brexpiprazole administration, and again on Day 10 after daily doses of either 4 mg (Cohorts 1 and 2), or 1 mg (Cohort 3). Cohort 1 received scans with [¹¹C]-(+)-PHNO to measure D₂ and D₃ receptor occupancy and [¹¹C]CUMI101 to measure 5-HT_1A occupancy; Cohort 2 received [¹¹C]MDL100907 for 5-HT_2A occupancy and [¹¹C]DASB for SERT occupancy; Cohort 3 underwent scanning with [¹¹C]-(+)-PHNO and [¹¹C]MDL100907. Five female and seven male subjects, aged 42 ± 8 years (range, 28-55 years), participated in this study. Dose dependency was observed at D₂ receptors, with occupancies reaching 64 ± 8% (mean +/- SD) following 1 mg/day and 80 ± 12% following 4 mg/day. D₃ receptor availability increased following 1 mg brexpiprazole treatment and did not change with 4 mg. Robust and dose-related occupancy was also observed at 5-HT_2A receptors. Negligible occupancy (<5%) was observed at 5-HT_1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D₂ receptors and 5-HT_2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D₃, 5-HT_1A receptors and SERT was not detectable with the radiotracers used for these targets. This pharmacologic profile is consistent with the observed antipsychotic and antidepressant effects.