Synthesis and preliminary evaluation of novel PET probes for GSK-3 imaging.

ABSTRACT

Non-invasive imaging of GSK-3 expression in the brain will help to understand the role of GSK-3 in disease pathology and progression. Herein, we report the radiosynthesis and evaluation of two novel isonicotinamide based 18F labeled PET probes, [18F]2 and [18F]6 for noninvasive imaging of GSK3. Among the developed PET probes, the in vitro blood-brain permeability coefficient of 2 (38 ± 20 × 10-6 cm/s, n = 3) was found to be better than 6 (8.75 ± 3.90 × 10-6 cm/s, n = 5). The reference compounds 2 and 6 showed nanomolar affinity towards GSK-3α and GSK-3ß. PET probe [18F]2 showed higher stability (100%) in mouse and human serums compared to [18F]6 (67.01 ± 4.93%, n = 3) in mouse serum and 66.20 ± 6.38%, n = 3) in human serum at 120 min post incubation. The in vivo imaging and blocking studies were performed in wild-type mice only with [18F]2 due to its observed stability. [18F]2 showed a SUV of 0.92 ± 0.28 (n = 6) in mice brain as early as 5 min post-injection followed by gradual clearance over time.