{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:05:40Z","timestamp":1789707940088,"version":"4.0.1"},"reference-count":145,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["7242265"],"award-info":[{"award-number":["7242265"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["7242265"],"award-info":[{"award-number":["7242265"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Glycogen synthase kinase-3\u03b2 (GSK-3\u03b2) serves as a crucial molecular target for Alzheimer\u2019s disease and other neurological disorders. Positron emission tomography (PET) enables non-invasive quantification of GSK-3\u03b2 in vivo, offering value for early diagnosis and mechanistic studies. However, despite two decades of effort, no GSK-3\u03b2 PET tracer has yet entered clinical trials. Methods: This review systematically summarizes the radiochemical synthesis and preclinical evaluation of major GSK-3\u03b2 tracer classes, comparing synthetic accessibility, target affinity, brain uptake, P-gp efflux, metabolic stability, radiometabolite profiles, and blocking experiments. The literature was systematically searched in PubMed and Web of Science databases (2005\u20132026). Several key obstacles impeding clinical progression of GSK-3\u03b2 PET radiotracers are identified. Results: First, P-gp efflux markedly reduces brain tracer accumulation, rendering even sub-nanomolar high-affinity ligands ineffective for brain imaging. Second, interfering factors such as brain-penetrant radiometabolites of [11C]OCM-44 and the extremely low plasma free fraction of [18F]OCM-50 greatly impair the quantitative accuracy of tracer uptake. Third, the paradoxical increase in brain uptake of isonicotinamide tracers upon blocking remains an unresolved confounding factor. Moreover, rodent data fail to reliably predict tracer performance in higher species, and to date, no tracer has been directly validated against GSK-3\u03b2 expression in patient brain tissue. Conclusions: This review proposes a tiered validation framework comprising four levels: assessment of P-gp efflux, metabolite-corrected arterial input function, low-affinity enantiomer controls, and human brain autoradiography. The framework provides a rigorous basis for screening candidates and a systematic reference for developing next-generation GSK-3\u03b2 PET tracers.<\/jats:p>","DOI":"10.3390\/ph19091457","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T13:05:26Z","timestamp":1789391126000},"page":"1457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Current Landscape of Glycogen Synthase Kinase-3\u03b2 PET Tracers: Progress, Limitations, and Perspectives\u2014A Narrative Review"],"prefix":"10.3390","volume":"19","author":[{"given":"Hualong","family":"Chen","sequence":"first","affiliation":[{"name":"Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingke","family":"Jiao","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Sun","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leyi","family":"Guan","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoran","family":"Niu","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boxin","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, No. 4, Fourth Section, North Ring Road, Chenghua District, Chengdu 610051, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3515-3827","authenticated-orcid":false,"given":"Zehui","family":"Wu","sequence":"additional","affiliation":[{"name":"Beijing Institute of Brain Disorders, Beijing Key Laboratory of Innovation and Translation of Central Nervous System Radiopharmaceuticals, Capital Medical University, Beijing 100069, China"},{"name":"Department of Nuclear Medicine, Tongren People\u2019s Hospital, Tongren 554300, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4631","DOI":"10.2174\/0929867329666220216113517","article-title":"Glycogen Synthase Kinase 3\u03b2 Involvement in Neuroinflammation and Neurodegenerative Diseases","volume":"29","author":"Gianferrara","year":"2022","journal-title":"Curr. 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