Development of [18F]Thiazolylacylaminopyridine-Based Glycogen synthase Kinase-3β ligands for positron emission tomography imaging

Glycogen synthase kinase-3 beta (GSK-3 beta) regulates numerous of CNS-specific signaling pathways, and is particularly implicated in various pathogenetic mechanisms of Alzheimer's disease (AD). A noninvasive method for detecting GSK-3 beta in AD brains via positron emission tomography (PET) imaging could enhance the understanding of AD pathogenesis and aid in the development of AD therapeutic drugs. In this study, an array of fluorinated thiazolyl acylaminopyridines (FTAAP) targeting GSK-3 beta were designed and synthesized. These compounds showed moderate to high affinities (IC50 = 6.0 - 426 nM) for GSK-3 beta in vitro. A potential GSK-3 beta tracer, [F-18]8, was successfully radiolabeled. [F-18]8 had unsatisfactory initial brain uptake despite its suitable lipophilicity, molecular size and good stability. Further structural refinement of the lead compound is needed to develop promising [F-18]-labeled radiotracers for the detection of GSK-3 beta in AD brains.