[¹⁸F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 23; pp. 9800 - 9805
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.06.2007; National Acad Sciences
• Subjects: Agonists; Amides - metabolism; Animals; Autoradiography; Biological Sciences; Boluses; Brain; Brain - anatomy & histology; Brain - metabolism; Brain research; cannabinoids; Cerebellum; cerebral cortex; clinical trials; Dosage; drugs; Emissions; Fluorine Radioisotopes; hippocampus; Humans; image analysis; Image Processing, Computer-Assisted; Imaging; in vivo studies; inhibitory concentration 50; Macaca mulatta; Male; males; Molecular Structure; Monkeys; Monkeys & apes; Neuroimaging; Neurology; Pharmacology; Placebos; Positron emission tomography; Positron-Emission Tomography - methods; Pyridines - metabolism; Radioactive Tracers; Receptor, Cannabinoid, CB1 - metabolism; Receptor, Cannabinoid, CB1 - ultrastructure; Receptors; Tomography
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0703472104

[¹⁸F]MK-9470 is a selective, high-affinity, inverse agonist (human IC₅₀, 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 [¹⁸F]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 [¹⁸F]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 [¹⁸F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [¹⁸F]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.