Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging
Gundam, S.R. et al. (2024) Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging. Sci. Rep. 14:15960. DOI:10.1038/s41598-024-65943-z
Glycogen synthase kinase (GSK-3) is a constitutively active serine/threonine protein kinase with nearly 100 protein substrates. GSK-3α and GSK-3β are involved in the regulation of numerous biological functions, including metabolism, cell signaling, apoptosis, proliferation, differentiation, and Wnt signaling pathways. Abnormal activities of GSK-3α/β are associated with diseases such as diabetes, inflammation, cancer, bipolar disorder, and neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s diseases. Overexpression of GSK-3α/β in Alzheimer’s disease (AD) leads to hyperphosphorylation of tau protein, resulting in neurofibrillary tangles, a hallmark of AD pathology.
Given the importance of GSK-3 in neurological disorders, imaging its expression and activity can elucidate its role in various pathophysiologies. Positron emission tomography (PET) imaging, with its high sensitivity, is ideal for visualizing and quantifying GSK-3 expression. Previous studies have explored small molecules radiolabeled with 11C for GSK-3 imaging, and efforts are ongoing to develop 18F-labeled GSK-3 radiotracers for longer studies.
This study reports the radiosynthesis and evaluation of two novel isonicotinamide-based 18F-labeled PET probes, [18F]2 and [18F]6, for GSK-3 imaging. The in vitro blood-brain permeability coefficient of [18F]2 was better than [18F]6. Reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3β. [18F]2 displayed higher stability in mouse and human serums compared to [18F]6. Due to its stability, in vivo imaging and blocking studies were performed only with [18F]2, showing an SUV of 0.92 ± 0.28 in mice brain at 5 minutes after injection, followed by gradual clearance over time. The results indicate [18F]2’s potential for further investigation in GSK-3–overexpressing models to evaluate its selectivity and retention in vivo.
Keywords: PET imaging, GSK-3, radiotracers, isonicotinamide, brain permeability, Alzheimer’s disease, neurodegenerative diseases, tau protein, cytochrome P450
