[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor
[18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor
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DOI：
10.1073/pnas.0703472104
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发表时间：
2007-06-05
影响因子：
11.1
通讯作者：
Hargreaves, Richard J.
中科院分区：
文献类型：
--
作者：
Burns, H. Donald;Van Laere, Koen;Hargreaves, Richard J.
[F-18]MK-9470是大麻素CB 1受体（CB 1 R）的选择性、高亲和力、反向激动剂（人IC 50，0.7 nM），已开发用于人脑成像。恒河猴脑中的放射自显影研究表明，[F-18]MK-9470结合与报告的CB 1受体分布一致，在大脑皮质、小脑、核/壳核、苍白球、黑质和海马中具有高特异性结合。在恒河猴中进行的正电子发射断层扫描（PET）成像研究显示，脑摄取较高，分布模式与放射自显影研究中观察到的分布模式基本一致。通过用有效的CB 1反向激动剂MK-0364预处理阻断摄取。壳核中总结合与非特异性结合的比例为4-5：1，表明存在强特异性信号，通过MK-0364置换研究证实该信号可逆。人体研究受试者的基线PET成像研究表明，[F-18]MK-9470的行为与猴中观察到的行为非常相似，具有非常好的重测变异性（7%）。在健康年轻男性受试者中进行的概念验证研究表明，MK-0364经口给药后，[F-18]MK-9470结合率呈剂量相关性降低，反映了药物对CB 1 R受体的占有率。因此，[F-18]MK-9470有可能成为一种有价值的非侵入性研究工具，用于人体各种神经精神疾病中CB 1 R生物学和药理学的体内研究。此外，它还可以证明靶点接合和非侵入性紧密占用研究，以帮助CB 1 R反向激动剂临床试验的剂量选择。
[F-18]MK-9470 is a selective, high-affinity, inverse agonist (human IC50,0.7 nM)for the cannabinoid CB1 receptor (CB1 R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [F-18]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, cauclate/putamen, globus pallidus, substantia nigra, and hippocampus. Positron emission tomography (PET) imaging studies in rhesus monkeys showed high brain uptake and a distribution pattern generally consistent with that seen in the autoradiographic studies. Uptake was blocked by pretreatment with a potent CB1 inverse agonist, MK-0364. The ratio of total to nonspecific binding in putamen was 4-5:1, indicative of a strong specific signal that was confirmed to be reversible via displacement studies with MK-0364. Baseline PET imaging studies in human research subject demonstrated behavior of [F-18]MK-9470 very similar to that seen in monkeys, with very good test-retest variability (7%). Proof of concept studies in healthy young male human subjects showed that MK-0364, given orally, produced a dose-related reduction in [F-18]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [F-18]MK-9470 has the potential to be a valuable, noninvasive research tool for the in vivo study of CB1R biology and pharmacology in a variety of neuropsychiatric disorders in humans. In addition, it allows demonstration of target engagement and noninvasive close-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.