دورية أكاديمية
Evaluation of [¹⁸F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human.
| العنوان: | Evaluation of [¹⁸F]MK-0911, a positron emission tomography (PET) tracer for opioid receptor-like 1 (ORL1), in rhesus monkey and human. |
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| المؤلفون: | Hostetler ED; Imaging, Merck Research Laboratories, West Point, PA 19486, USA. eric_hostetler@merck.com, Sanabria-Bohórquez S, Eng W, Joshi AD, Patel S, Gibson RE, O'Malley S, Krause SM, Ryan C, Riffel K, Bi S, Okamoto O, Kawamoto H, Ozaki S, Ohta H, de Groot T, Bormans G, Depré M, de Hoon J, De Lepeleire I, Reynders T, Cook JJ, Burns HD, Egan M, Cho W, van Laere K, Hargreaves RJ |
| المصدر: | NeuroImage [Neuroimage] 2013 Mar; Vol. 68, pp. 1-10. Date of Electronic Publication: 2012 Dec 11. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 9215515 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9572 (Electronic) Linking ISSN: 10538119 NLM ISO Abbreviation: Neuroimage Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Orlando, FL : Academic Press, c1992- |
| مواضيع طبية MeSH: | Benzimidazoles/*pharmacokinetics , Brain/*diagnostic imaging , Fluorine Radioisotopes/*pharmacokinetics , Piperidines/*pharmacokinetics , Positron-Emission Tomography/*methods , Radiopharmaceuticals/*pharmacokinetics , Receptors, Opioid/*metabolism, Adult ; Animals ; Benzimidazoles/chemistry ; Brain/metabolism ; Fluorine Radioisotopes/chemistry ; Humans ; Macaca mulatta ; Male ; Middle Aged ; Piperidines/chemistry ; Radiopharmaceuticals/chemistry ; Tissue Distribution ; Young Adult ; Nociceptin Receptor |
| مستخلص: | Antagonism of the central opioid receptor like-1 receptor (ORL1) has been implicated in cognition, and has been a focus of drug discovery efforts to ameliorate the cognitive deficits that remain during the stable treatment of schizophrenia with current antipsychotics. In order to facilitate dose selection for phase II clinical testing an ORL1-specific PET tracer was developed to determine drug plasma concentration versus occupancy relationships in order to ensure that the doses selected and the degree of target engagement were sufficient to ensure adequate proof of concept testing. MK-0911 is a selective, high affinity antagonist for the ORL1 receptor radiolabeled with high specific activity (18)F for positron emission tomography (PET) studies. Evaluation of [(18)F]MK-0911 in rhesus monkey PET studies showed a pattern of brain uptake which was consistent with the known distribution of ORL1. In vitro autoradiography with [(18)F]MK-0911 in rhesus monkey and human brain tissue slices showed a regional distribution that was consistent with in vivo imaging results in monkey. Pre-treatment of rhesus monkeys with high doses of structurally diverse ORL1 antagonists MK-0584, MK-0337, or MK-5757 achieved blockade of [(18)F]MK-0911 in all gray matter regions. Baseline PET studies with [(18)F]MK-0911 in healthy human subjects showed tracer distribution and kinetics similar to that observed in rhesus monkey. Quantification of [(18)F]MK-0911 uptake in repeat human baseline PET studies showed a test-retest variability in volume of distribution (V(T)) averaging 3% across brain regions. Humans dosed orally with MK-5757 showed reduced [(18)F]MK-0911 tracer concentration in brain proportional with MK-5757 dose and plasma level. [(18)F]MK-0911 was useful for determining MK-5757-induced receptor occupancy of ORL1 to guide MK-5757 dose-selection for clinical proof-of-concept studies. Additionally, [(18)F]MK-0911 may be a useful tool for studying the pharmacology of ORL1 in various human populations and disease states. (Copyright © 2012 Elsevier Inc. All rights reserved.) |
| المشرفين على المادة: | 0 (Benzimidazoles) 0 (Fluorine Radioisotopes) 0 (MK-0911) 0 (Piperidines) 0 (Radiopharmaceuticals) 0 (Receptors, Opioid) 0 (Nociceptin Receptor) |
| تواريخ الأحداث: | Date Created: 20121215 Date Completed: 20130801 Latest Revision: 20221207 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.neuroimage.2012.11.053 |
| PMID: | 23238431 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1095-9572 |
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| DOI: | 10.1016/j.neuroimage.2012.11.053 |