A positron emission tomography occupancy study of brexpiprazole at dopamine D2 and D3 and serotonin 5-HT1A and 5-HT2A receptors, and serotonin reuptake transporters in subjects with schizophrenia

Abstract

The objective of this study (NCT01854944) was to assess D2/D3, 5-HT1A, 5-HT2A 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-HT1A occupancy; Cohort 2 received [11C]MDL100907 for 5-HT2A 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-HT2A receptors. Negligible occupancy (<5%) was observed at 5-HT1A and SERT at 4 mg/day. In summary, brexpiprazole demonstrated in vivo binding to D2 receptors and 5-HT2A receptors at steady state after 10 days of daily administration in a dose dependent manner, while binding to D3, 5-HT1A 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.

Figures

Fig. 1. Receptor Occupancy Fits With Parameter Estimates.

One parameter model fits (EC50 only, model 1). D2 receptor (left), and 5-HT2A receptor (right) measured occupancy vs measured plasma brexpiprazole concentration from PK analysis. Plasma brexpiprazole levels are the concentrations closest in time to the PET scan.