Abstract
AbstractGlycogen synthase kinase‐3 α/β 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‐3α/β in the brain to understand the pathogenesis of AD. Herein, we synthesized two PET probes, [18F]F‐CNBI and [18F]F‐CNPIFE, and evaluated their BBB permeability and affinity towards GSK‐3α/β. [19F]F‐CNPIFE showed higher in‐vitro binding towards GSK‐3α/β (IC50=19.4±2.5 nM; n=3, for GSK‐3α, IC50=19.4±3.8 nM; n=3, for GSK‐3β) compared to [19F]F‐CNBI (IC50=107.6±26.0 nM; n=4, for GSK‐3α, IC50=105.3±18.2 nM; n=3, for GSK‐3β). [18F]F‐CNPIFE showed 9.5‐fold higher brain uptake than [18F]F‐CNBI, in normal FVB/NJ mice, which was increased by additional 1.5‐fold on co‐administration of [19F]F‐CNPIFE with respect to [18F]F‐CNBI. Overall, [18F]F‐CNPIFE is a promising PET probe for GSK‐3α/β imaging and warrants further evaluation in an AD mouse model.
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