Radiosynthesis and Evaluation of 11C-Labeled Imidazolyl Pyrimidine Derivatives for Positron Emission Tomography Imaging of Glycogen Synthase Kinase-3

High Resolution Image Download MS PowerPoint Slide Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that regulates various biological processes by phosphorylating protein substrates. Dysregulation of GSK-3 is linked to a variety of diseases, including malignancies, diabetes, and neurodegenerative disorders. Moreover, GSK-3 hyperactivity is a potential contributing factor in Alzheimer’s disease, suggesting that GSK-3 inhibition may offer therapeutic benefits. Herein, we report the synthesis and evaluation of five 11 C-labeled imidazolyl pyrimidine analogues [ 11 C] 13a – e (codenamed AZ12646326, AZ12646603, AZ12656261, AZ12977360, and AZ12943203) as novel radioligands for positron emission tomography (PET) imaging of GSK-3. Pharmacological assays showed that compounds 13a – e exhibited high in vitro binding affinity to GSK-3β, with K i values ranging from 2.49 to 4.95 nM. In vitro autoradiography confirmed high levels of specific binding in GSK-3-rich regions of the rodent brain, highlighting the promising imaging properties of these analogues. Radiosynthesis of [ 11 C] 13a – e was achieved via palladium-promoted carbonylation reactions with [ 11 C]carbon monoxide, with excellent radiochemical purity (>99%). However, PET imaging studies in nonhuman primates in vivo showed low brain uptake of these radioligands, and [ 11 C] 13e was identified as a P -glycoprotein substrate. This study offers valuable insights for optimizing future GSK-3-targeted PET tracers based on the imidazolyl pyrimidine scaffold.