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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Jewell, James P. De Hoon, Jan Hamill, Terence G. Lin, Linus S. Hagmann, William K. Vanko, Amy Gibson, Ray Wagner, John A. Hargreaves, Richard J. Van Hecken, Anne Liu, Ping Krause, Stephen Gottesdiener, Keith Sanabria-bohórquez, Sandra Eng, Wai-si De Lepeleire, Inge Burns, H. Donald Goulet, Mark T. Ryan, Christine Mortelmans, Luc Patel, Shil Fong, Tung M. Van Laere, Koen Rothenberg, Paul Stoch, S. Aubrey Connolly, Brett Dupont, Patrick Cote, Josee Bormans, Guy |
| Description | Author Affiliation: Burns HD ( Imaging Research, Merck Research Laboratories, West Point, PA 19486, USA. donald_burns@merck.com); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 23 |
| Volume Number | 104 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2007-06-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Brain Anatomy & Histology Positron-Emission Tomography Radioactive Tracers Receptor, Cannabinoid, CB1 Ultrastructure Amides Metabolism Animals Autoradiography Fluorine Radioisotopes Image Processing, Computer-Assisted Macaca Mulatta Molecular Structure Pyridines Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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