[¹⁸F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor
[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...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 104; no. 23; pp. 9800 - 9805 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
05.06.2007
National Acad Sciences |
| Subjects | |
| Online Access | Get full text |
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| Abstract | [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. |
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| AbstractList | [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. [...F]MK-9470 is a selective, high-affinity, inverse agonist (human IC..., 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 [...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 [...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 [...F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [...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. (ProQuest-CSA LLC: ... denotes formulae/symbols omitted.) [ 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. inverse agonist occupancy [ 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. [ super(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC sub(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 [ super(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 [ super(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 [ super(18)F]MK-9470 binding reflecting CB1R receptor occupancy by the drug. Thus, [ super(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. [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 neuropsychiatrie 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. [(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. |
| Author | Sanabria-Bohórquez, Sandra Goulet, Mark T Vanko, Amy Gibson, Ray Fong, Tung M Jewell, James P Van Hecken, Anne Liu, Ping Krause, Stephen Hargreaves, Richard J Gottesdiener, Keith Eng, Wai-si Hamill, Terence G De Lepeleire, Inge Burns, H. Donald de Hoon, Jan Ryan, Christine Hagmann, William K Lin, Linus S Mortelmans, Luc Patel, Shil Van Laere, Koen Rothenberg, Paul Stoch, S. Aubrey Connolly, Brett Wagner, John A Dupont, Patrick Cote, Josee Bormans, Guy |
| Author_xml | – sequence: 1 fullname: Burns, H. Donald – sequence: 2 fullname: Van Laere, Koen – sequence: 3 fullname: Sanabria-Bohórquez, Sandra – sequence: 4 fullname: Hamill, Terence G – sequence: 5 fullname: Bormans, Guy – sequence: 6 fullname: Eng, Wai-si – sequence: 7 fullname: Gibson, Ray – sequence: 8 fullname: Ryan, Christine – sequence: 9 fullname: Connolly, Brett – sequence: 10 fullname: Patel, Shil – sequence: 11 fullname: Krause, Stephen – sequence: 12 fullname: Vanko, Amy – sequence: 13 fullname: Van Hecken, Anne – sequence: 14 fullname: Dupont, Patrick – sequence: 15 fullname: De Lepeleire, Inge – sequence: 16 fullname: Rothenberg, Paul – sequence: 17 fullname: Stoch, S. Aubrey – sequence: 18 fullname: Cote, Josee – sequence: 19 fullname: Hagmann, William K – sequence: 20 fullname: Jewell, James P – sequence: 21 fullname: Lin, Linus S – sequence: 22 fullname: Liu, Ping – sequence: 23 fullname: Goulet, Mark T – sequence: 24 fullname: Gottesdiener, Keith – sequence: 25 fullname: Wagner, John A – sequence: 26 fullname: de Hoon, Jan – sequence: 27 fullname: Mortelmans, Luc – sequence: 28 fullname: Fong, Tung M – sequence: 29 fullname: Hargreaves, Richard J |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/17535893$$D View this record in MEDLINE/PubMed |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23 Author contributions: H.D.B., K.V.L., S.S.-B., T.G.H., W.-s.E., R.G., C.R., P.R., S.A.S., J.C., W.K.H., J.P.J., L.S.L., P.L., M.T.G., K.G., J.A.W., T.M.F., and R.J.H. designed research; K.V.L., S.S.-B., T.G.H., G.B., W.-s.E., R.G., C.R., B.C., S.P., S.K., A.V., A.V.H., P.D., I.D.L., W.K.H., J.P.J., L.S.L., P.L., M.T.G., J.d.H., and L.M. performed research; T.G.H. and G.B. contributed new reagents/analytic tools; H.D.B., S.S.-B., G.B., W.-s.E., R.G., B.C., S.P., A.V., P.R., S.A.S., J.C., K.G., T.M.F., and R.J.H. analyzed data; and H.D.B., K.V.L., S.S.-B., T.G.H., G.B., W.-s.E., R.G., C.R., B.C., A.V.H., P.D., I.D.L., S.A.S., K.G., J.A.W., J.d.H., L.M., T.M.F., and R.J.H. wrote the paper. Communicated by Michael E. Phelps, University of California School of Medicine, Los Angeles, CA, April 20, 2007 |
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| Snippet | [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... [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... [ 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... [ 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... [(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... [...F]MK-9470 is a selective, high-affinity, inverse agonist (human IC..., 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed for use in... [ super(18)F]MK-9470 is a selective, high-affinity, inverse agonist (human IC sub(50), 0.7 nM) for the cannabinoid CB1 receptor (CB1R) that has been developed... |
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| SubjectTerms | 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 |
| Title | [¹⁸F]MK-9470, a positron emission tomography (PET) tracer for in vivo human PET brain imaging of the cannabinoid-1 receptor |
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