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In Vitro and In Vivo Evaluation of GSK‑3 Radioligands in Alzheimer’s Disease: Preliminary Evidence of Sex Differences

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journal contribution
posted on 20.07.2021, 19:08 by Ashley C. Knight, Cassis Varlow, Junchao Tong, Neil Vasdev
Glycogen synthase kinase-3 (GSK-3) is a positron emission tomography (PET) imaging target with implications in the pathogenesis of Alzheimer’s disease (AD). This preliminary study evaluates human AD and transgenic P301L mouse brain tissues using the GSK-3-targeting radiotracers [3H]­PF-367 and [3H]­OCM-44 in radioligand binding assays. A saturation analysis showed decreased GSK-3 density in female human AD compared to a normal healthy brain. Equivalence in density (Bmax), affinity (Kd), and apparent affinity (Ki) of both radiotracers was demonstrated to enable their interchangeability for in vitro evaluations of GSK-3 expression. An evaluation of P301L mouse brain by [3H]/[11C]­OCM-44 delineated differences in the Bmax of GSK-3 between the control and transgenic mice within male subjects. PET imaging showed similar trends to those observed in vitro. Sex differences are revealed as a potential parameter to consider in the development of GSK-3-targeted diagnostics and therapeutics and could guide recruitment for clinical studies.