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The goal of this work was to evaluate two leading GSK-3 positron emission tomography (PET) radioligands, [11C]OCM-44 and [18F]OCM-50, in non-human primates to assess their potential for clinical translation. A total of nine PET scans were performed with the two radiotracers using arterial blood sampling in adult rhesus macaques. Brain regional time-activity curves were extracted and fitted with one- and two-tissue compartment models using metabolite-corrected arterial input functions. Target selectivity was assessed after pre-administration of the GSK-3 inhibitor PF-04802367 (PF-367, 0.03\u20130.25 mg\/kg). Both radiotracers showed good brain uptake and distribution throughout grey matter. [11C]OCM-44 had a free fraction in the plasma of 3% at baseline and was metabolized quickly. The [11C]OCM-44 volume of distribution (VT) values in the brain increased with time; VT values from models fitted to truncated 60-min scan data were 1.4\u20132.9 mL\/cm3 across brain regions. The plasma free fraction was 0.6% for [18F]OCM-50 and VT values (120-min) were 0.39\u20130.87 mL\/cm3 in grey matter regions. After correcting for plasma free fraction increases during blocking scans, reductions in regional VT indicated &gt;80% target occupancy by 0.1 mg\/kg of PF-367 for both radiotracers, supporting target selectivity in vivo. [11C]OCM-44 and [18F]OCM-50 warrant further evaluation as radioligands for imaging GSK-3 in the brain, though radio-metabolite accumulation may confound image analysis.<\/jats:p>","DOI":"10.3390\/ph16020194","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T02:54:37Z","timestamp":1675047277000},"page":"194","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In Vivo Imaging and Kinetic Modeling of Novel Glycogen Synthase Kinase-3 Radiotracers [11C]OCM-44 and [18F]OCM-50 in Non-Human Primates"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4775-6943","authenticated-orcid":false,"given":"Kelly","family":"Smart","sequence":"first","affiliation":[{"name":"Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Qiang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Holden","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary","family":"Felchner","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zhang","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjiang","family":"Han","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"},{"name":"Nanfang Hospital, Southern Medical University, 1838 Guangzhou Blvd North, Guangzhou 510515, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jim","family":"Ropchan","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9338-7966","authenticated-orcid":false,"given":"Richard E.","family":"Carson","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2087-5125","authenticated-orcid":false,"given":"Neil","family":"Vasdev","sequence":"additional","affiliation":[{"name":"Brain Health Imaging Centre, Centre for Addiction and Mental Health, 250 College St., Toronto, ON M5T 1R8, Canada"},{"name":"Department of Psychiatry, University of Toronto, 250 College St., Toronto, ON M5T 1R8, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6757-3220","authenticated-orcid":false,"given":"Yiyun","family":"Huang","sequence":"additional","affiliation":[{"name":"Yale PET Center, Yale School of Medicine, 801 Howard Ave., New Haven, CT 06519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. 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