title: [18F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor.
abstract: [(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.
authors.affiliation: Imaging Research, Merck Research Laboratories, West Point, PA 19486, USA. donald_burns@merck.com
authors.forename: H Donald
authors.initials: HD
authors.lastname: Burns
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authors.lastname: Van Laere
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authors.lastname: Sanabria-Bohórquez
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authors.lastname: Vanko
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authors.lastname: Van Hecken
authors.forename: Patrick
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authors.lastname: Dupont
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authors.lastname: De Lepeleire
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authors.forename: James P
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authors.forename: Linus S
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authors.lastname: Lin
authors.forename: Ping
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authors.lastname: Liu
authors.forename: Mark T
authors.initials: MT
authors.lastname: Goulet
authors.forename: Keith
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authors.lastname: Gottesdiener
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Jan
authors.initials: J
authors.lastname: de Hoon
authors.forename: Luc
authors.initials: L
authors.lastname: Mortelmans
authors.forename: Tung M
authors.initials: TM
authors.lastname: Fong
authors.forename: Richard J
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mesh_terms: D000577:Amides / Q000378:metabolism; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D011725:Pyridines / Q000378:metabolism; D011849:Radioactive Tracers; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism / Q000648:ultrastructure*
chemical_list: D000577:Amides; D005462:Fluorine Radioisotopes; D011725:Pyridines; D011849:Radioactive Tracers; D043884:Receptor, Cannabinoid, CB1; C521311:N-(3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl)-2-methyl-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)propanamide