Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2007-06, Vol.104 (23), p.9800-9805

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• [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.