Current Landscape of Glycogen Synthase Kinase-3β PET Tracers: Progress, Limitations, and Perspectives-A Narrative...

Background/Objectives: Glycogen synthase kinase-3β (GSK-3β) serves as a crucial molecular target for Alzheimer's disease and other neurological disorders. Positron emission tomography (PET) enables non-invasive quantification of GSK-3β in vivo, offering value for early diagnosis and mechanistic studies. However, despite two decades of effort, no GSK-3β PET tracer has yet entered clinical trials. Methods: This review systematically summarizes the radiochemical synthesis and preclinical evaluation of major GSK-3β 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 (2005-2026). Several key obstacles impeding clinical progression of GSK-3β 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-3β 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-3β PET tracers.