Open AccessIn Vitro and In Vivo Evaluation of GSK-3 Radioligands in Alzheimer’s Disease: Preliminary Evidence of Sex Differences
Author(s) -
Ashley Knight,
Cassis Varlow,
Junchao Tong,
Neil Vasdev
Publication year - 2021
Publication title -
acs pharmacology and translational science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.271
H-Index - 10
ISSN - 2575-9108
DOI - 10.1021/acsptsci.1c00132
Subject(s) - radioligand , in vivo , in vitro , gsk 3 , binding potential , positron emission tomography , genetically modified mouse , human brain , medicine , biology , neuroscience , kinase , transgene , pathology , endocrinology , biochemistry , gene , genetics
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 [ 3 H]PF-367 and [ 3 H]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 [ 3 H]/[ 11 C]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.