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

Abstract

Glycogen synthase kinase-3β (GSK-3β) 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-3β 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-3β were designed and synthesized. These compounds showed moderate to high affinities (IC50 = 6.0 - 426 nM) for GSK-3β in vitro. A potential GSK-3β tracer, [18F]8, was successfully radiolabeled. [18F]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 [18F]-labeled radiotracers for the detection of GSK-3β in AD brains.

• Authors: Jianhua Jia, Lan Yi, Zhu Xia, Meixian Yang, Dachuan Qiu, Zhenghuan Zhao, Zhiping Peng
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 88 Pg. 129263 (05 15 2023) ISSN: 1464-3405 [Electronic] England
• PMID: 37004924 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Elsevier Ltd. All rights reserved.

Chemical References

• Glycogen Synthase Kinase 3 beta
• Ligands

Topics

• Humans
• Glycogen Synthase Kinase 3 beta (metabolism)
• Ligands
• Brain (diagnostic imaging, metabolism)
• Alzheimer Disease (diagnostic imaging, metabolism)
• Positron-Emission Tomography (methods)
• Phosphorylation