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

作者：Zhong, Yuhua; Yang, Shaoxi; Cui, Jianyu; Wang, Jie; Li, Lin; Chen, Yilin; Chen, Junjie; Feng, Pengju; Huang, Shun; Li, Hongsheng; Han, Yanjian; Tang, Ganghua; Hu, Kongzhen^*

来源：MOLECULAR PHARMACEUTICS, 2021, 18(3): 1277-1284.

DOI：10.1021/acs.molpharmaceut.0c01133

• GSK-3 beta
• PET
• F-18-labeled
• isonicotinamide
• brain

Glycogen synthase kinase-3 beta (GSK-3 beta), 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-3 beta could aid in investigating GSK-3 beta 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-3 beta. After extensive in vitro inhibitory activity assays and analyzing U87 cell uptake, we identified [F-18]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 [F-18]10b-d penetrated the blood-brain barrier and accumulated in GSK-3 beta-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 F-18-labeled GSK-3 beta PET probes.

• 单位
  南方医科大学; i; 5