Development of [18F]Thiazolylacylaminopyridine-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.
Development of [18F]Thiazolylacylaminopyridine-Based Glycogen Synthase Kinase-3β Ligands for Positron Emission Tomography Imaging.
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DOI：
10.1016/j.bmcl.2023.129263
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发表时间：
2023-03
影响因子：
2.7
通讯作者：
Jianhua Jia;Lan-Juan Yi;Zhu Xia;Meixian Yang;Dachuan Qiu;Zhenghuan Zhao;Z. Peng
中科院分区：
文献类型：
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作者：
Jianhua Jia;Lan-Juan Yi;Zhu Xia;Meixian Yang;Dachuan Qiu;Zhenghuan Zhao;Z. Peng
糖原合成酶激酶-3 β（Glycogen synthase kinase-3 β，GSK-3β）参与调节中枢神经系统特异性信号通路，尤其参与阿尔茨海默病（Alzheimer's disease，AD）的多种发病机制。通过正电子发射断层扫描（PET）成像检测AD脑组织中GSK-3β的无创性方法可以提高对AD发病机制的认识，并有助于AD治疗药物的开发。本研究设计并合成了一系列以GSK-3β为靶点的含氟噻唑酰氨基吡啶（FTAAP）。这些化合物在体外对GSK-3β显示出中等至高亲和力（IC 50 = 6.0 - 426 nM）。成功放射性标记了潜在的GSK-3β示踪剂[18 F]8。[18F] 8具有合适的亲脂性、分子大小和良好的稳定性，但其初始脑摄取并不令人满意。需要对先导化合物进行进一步的结构优化，以开发有前景的[18 F]标记放射性示踪剂，用于检测AD脑中的GSK-3β。
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-3βin vitro. A potential GSK-3β tracer, [18F]8, was successfully radiolabeled. [18F]8had 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.