Comparison of [F-18]F-CNBI and [F-18]F-CNPIFE as Positron Emission Tomography Probes for Noninvasive Imaging of Glycogen Synthase Kinase-3 in Normal Mice

Glycogen synthase kinase-3 alpha/beta is involved in dysregulation of neuronal tau protein in Alzheimer's disease (AD). There is an unmet clinical need for a blood-brain barrier (BBB) permeable positron emission tomography (PET) probe for imaging of GSK-3 alpha/beta in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [F-18]F-CNBI and [F-18]F-CNPIFE, and evaluated their BBB permeability and affinity towards GSK-3 alpha/beta. [F-19]F-CNPIFE showed higher in-vitro binding towards GSK-3 alpha/beta (IC50=19.4 +/- 2.5 nM; n=3, for GSK-3 alpha, IC50=19.4 +/- 3.8 nM; n=3, for GSK-3 beta) compared to [F-19]F-CNBI (IC50=107.6 +/- 26.0 nM; n=4, for GSK-3 alpha, IC50=105.3 +/- 18.2 nM; n=3, for GSK-3 beta). [F-18]F-CNPIFE showed 9.5-fold higher brain uptake than [F-18]F-CNBI, in normal FVB/NJ mice, which was increased by additional 1.5-fold on co-administration of [F-19]F-CNPIFE with respect to [F-18]F-CNBI. Overall, [F-18]F-CNPIFE is a promising PET probe for GSK-3 alpha/beta imaging and warrants further evaluation in an AD mouse model.