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Novel 18F‑Labeled Isonicotinamide-Based Radioligands for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3β

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journal contribution
posted on 25.01.2021, 19:10 by Yuhua Zhong, Shaoxi Yang, Jianyu Cui, Jie Wang, Lin Li, Yilin Chen, Junjie Chen, Pengju Feng, Shun Huang, Hongsheng Li, Yanjian Han, Ganghua Tang, Kongzhen Hu
Glycogen synthase kinase-3β (GSK-3β), a cytoplasmic serine/threonine protein kinase, is involved in several human pathologies including Alzheimer’s disease, bipolar disorder, diabetes, and cancer. Positron emission tomography (PET) imaging of GSK-3β could aid in investigating GSK-3β levels under normal and pathological conditions. In this study, we designed and synthesized fluorinated PET radioligands starting with recently identified isonicotinamide derivatives that showed potent affinity to GSK-3β. After extensive in vitro inhibitory activity assays and analyzing U87 cell uptake, we identified [18F]10a–d as potential tracers with good specificity and high affinity. They were then subjected to further in vivo evaluation in rodent brain comprising PET imaging and metabolism studies. The radioligands [18F]10b–d penetrated the blood–brain barrier and accumulated in GSK-3β-rich regions, including amygdala, cerebellum, and hippocampus. Also, it could be specifically blocked using the corresponding standard compounds. With these results, this work sets the basis for further development of novel 18F-labeled GSK-3β PET probes.