Evaluation of [18F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human
Evaluation of [18F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human
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DOI：
10.1016/j.neuroimage.2012.11.053
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发表时间：
2013-03-01
期刊：
影响因子：
5.7
通讯作者：
Hargreaves, Richard J.
中科院分区：
文献类型：
--
作者：
Hostetler, Eric D.;Sanabria-Bohorquez, Sandra;Hargreaves, Richard J.
中枢阿片样受体样-1受体（ORL 1）的拮抗作用与认知有关，并且一直是药物发现努力的焦点，以改善在用当前抗精神病药稳定治疗精神分裂症期间仍然存在的认知缺陷。为了便于II期临床试验的剂量选择，开发了一种ORL 1特异性PET示踪剂，以确定药物血浆浓度与占用率的关系，从而确保所选剂量和靶点接合程度足以确保充分的概念验证试验。MK-0911是一种选择性、高亲和力的ORL 1受体拮抗剂，经高比活度F-18放射性标记，用于正电子发射断层扫描（PET）研究。在恒河猴PET研究中对[F-18]MK-0911的评价显示，脑摄取模式与ORL 1的已知分布一致。[F-18]MK-0911在恒河猴和人脑组织切片中的体外放射自显影显示出与猴体内成像结果一致的区域分布。用高剂量结构不同的ORL 1拮抗剂MK-0584、MK-0337或MK-5757预处理恒河猴，在所有灰质区域实现了[F-18]MK-0911的阻断。在健康人类受试者中进行的[F-18]MK-0911基线PET研究显示，示踪剂分布和动力学与在恒河猴中观察到的结果相似。重复人体基线PET研究中[F-18]MK-0911摄取的定量显示，分布容积（V-T）的重测变异性在脑区中平均为3%。经口给予MK-5757的人显示脑中[F-18]MK-0911示踪剂浓度降低，与MK-5757剂量和血浆水平成比例。[F-18]MK-0911可用于测定MK-5757诱导的ORL 1受体占有率，以指导临床概念验证研究的MK-5757剂量选择。此外，[F-18]MK-0911可能是研究ORL 1在各种人群和疾病状态中的药理学的有用工具。(C)2012 Elsevier Inc. All rights reserved.
Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity F-18 for positron emission tomography (PET) studies. Evaluation of [F-18]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [F-18]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [F-18]MK-0911 in all gray matter regions. Baseline PET studies with [F-18]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [F-18]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V-T) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [F-18]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [F-18]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [F-18]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states. (C) 2012 Elsevier Inc. All rights reserved.