In Vitro and In Vivo Evaluation of GSK-3 Radioligands in Alzheimer's Disease: Preliminary Evidence of Sex Differences.

Abstract

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 (B max), affinity (K d), and apparent affinity (K i) 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 B max 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.