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.

中文翻译：

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一项正电子发射断层扫描对精神分裂症受试者中布瑞哌唑在多巴胺 D2 和 D3 以及血清素 5-HT1A 和 5-HT2A 受体以及血清素再摄取转运蛋白上的占据研究。


本研究 (NCT01854944) 的目的是评估成年精神分裂症受试者中布瑞哌唑的 D2/D3、5-HT1A、5-HT2A 和血清素转运蛋白 (SERT) 占有率，以确定可能与该药物的抗精神病药、抗抑郁药和副作用。受试者被分为三个独立的队列，每个队列有四名受试者。所有受试者在 brexpiprmaze 给药前基线时均使用两种不同的放射性示踪剂进行正电子发射断层扫描 (PET) 扫描，并在每日剂量 4 mg（队列 1 和 2）或 1 mg（队列 3）后第 10 天再次进行。第 1 组接受 [11C]-(+)-PHNO 扫描以测量 D2 和 D3 受体占用率，并使用 [11C]CUMI101 扫描以测量 5-HT1A 占用率；第 2 组接受 [11C]MDL100907 进行 5-HT2A 占用，并接受 [11C]DASB 进行 SERT 占用；第 3 组接受 [11C]-(+)-PHNO 和 [11C]MDL100907 扫描。年龄 42 ± 8 岁（范围 28-55 岁）的 5 名女性和 7 名男性受试者参与了这项研究。在 D2 受体处观察到剂量依赖性，在 1 mg/天后，占有率达到 64 ± 8%（平均值 +/- SD），在 4 mg/天后，占有率达到 80 ± 12%。 1 mg 布瑞哌唑治疗后 D3 受体的可用性增加，而 4 mg 治疗后 D3 受体的可用性没有变化。在 5-HT2A 受体上也观察到了稳健且与剂量相关的占据。在 5-HT1A 和 4 mg/天的 SERT 中观察到可忽略不计的占用率 (<5%)。总之，每日给药 10 天后，brexpiprmaze 在体内以剂量依赖性方式在稳态下与 D2 受体和 5-HT2A 受体结合，而与 D3、5-HT1A 受体和 SERT 的结合用用于放射性示踪剂的放射性示踪剂检测不到。这些目标。 该药理学特征与观察到的抗精神病和抗抑郁作用一致。