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

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

doi:10.1073/pnas.0703472104

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

Author:

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

Keywords:

Amides, Animals, Autoradiography, Brain, Fluorine Radioisotopes, Humans, Image Processing, Computer-Assisted, Macaca mulatta, Male, Molecular Structure, Positron-Emission Tomography, Pyridines, Radioactive Tracers, Receptor, Cannabinoid, CB1, Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, inverse agonist occupancy, LEVODOPA-INDUCED DYSKINESIA, CB1 RECEPTORS, ENDOCANNABINOID SYSTEM, PARKINSONS-DISEASE, BASAL GANGLIA, LOCALIZATION, BINDING, VITRO, INTERNALIZATION, RADIOLIGAND

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.