Burns H Donald, Van Laere Koen, Sanabria-Bohórquez Sandra, Hamill Terence G, Bormans Guy, Eng Wai-si, Gibson Ray, Ryan Christine, Connolly Brett, Patel Shil, Krause Stephen, Vanko Amy, Van Hecken Anne, Dupont Patrick, De Lepeleire Inge, Rothenberg Paul, Stoch S Aubrey, Cote Josee, Hagmann William K, Jewell James P, Lin Linus S, Liu Ping, Goulet Mark T, Gottesdiener Keith, Wagner John A, de Hoon Jan, Mortelmans Luc, Fong Tung M, Hargreaves Richard J
Imaging Research, Merck Research Laboratories, West Point, PA 19486, USA.
Proc Natl Acad Sci U S A. 2007 Jun 5;104(23):9800-5. doi: 10.1073/pnas.0703472104. Epub 2007 May 29.
[(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in human brain imaging. Autoradiographic studies in rhesus monkey brain showed that [(18)F]MK-9470 binding is aligned with the reported distribution of CB1 receptors with high specific binding in the cerebral cortex, cerebellum, caudate/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 [(18)F]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 [(18)F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [(18)F]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 dose-occupancy studies to aid in dose selection for clinical trials of CB1R inverse agonists.
[18F]MK-9470是一种用于人脑成像的、对大麻素CB1受体（CB1R）具有选择性、高亲和力的反向激动剂（人IC50为0.7 nM）。对恒河猴脑进行的放射自显影研究表明，[18F]MK-9470的结合与报道的CB1受体分布一致，在大脑皮质、小脑、尾状核/壳核、苍白球、黑质和海马体中有高特异性结合。对恒河猴进行的正电子发射断层扫描（PET）成像研究显示，脑部摄取量高，分布模式总体上与放射自显影研究中所见一致。摄取被一种强效CB1反向激动剂MK-0364预处理所阻断。壳核中总结合与非特异性结合的比率为4-5:1，表明有很强的特异性信号，通过用MK-0364进行置换研究证实该信号是可逆的。在人类研究对象中进行的基线PET成像研究表明，[18F]MK-9470的行为与在猴子中所见非常相似，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，口服MK-0364会使[18F]MK-9470的结合产生与剂量相关的减少，反映出该药物对CB1R受体的占据情况。因此，[18F]MK-9470有潜力成为一种有价值的非侵入性研究工具，用于在体内研究人类各种神经精神疾病中的CB1R生物学和药理学。此外，它还能进行靶点结合展示和非侵入性剂量-占据研究，以帮助为CB1R反向激动剂的临床试验选择剂量。
