Synthesis and Initial in Vivo Studies with [(11)C]SB-216763: The First Radiolabeled Brain Penetrative Inhibitor of GSK-3.

Quantifying glycogen synthase kinase-3 (GSK-3) activity in vivo using positron emission tomography (PET) imaging is of interest because dysregulation of GSK-3 is implicated in numerous diseases and neurological disorders for which GSK-3 inhibitors are being considered as therapeutic strategies. Previous PET radiotracers for GSK-3 have been reported, but none of the published examples cross the blood-brain barrier. Therefore, we have an ongoing interest in developing a brain penetrating radiotracer for GSK-3. To this end, we were interested in synthesis and preclinical evaluation of [(11)C]SB-216763, a high-affinity inhibitor of GSK-3 (K i = 9 nM; IC50 = 34 nM). Initial radiosyntheses of [(11)C]SB-216763 proved ineffective in our hands because of competing [3 + 3] sigmatropic shifts. Therefore, we have developed a novel one-pot two-step synthesis of [(11)C]SB-216763 from a 2,4-dimethoxybenzyl-protected maleimide precursor, which provided high specific activity [(11)C]SB-216763 in 1% noncorrected radiochemical yield (based upon [(11)C]CH3I) and 97-100% radiochemical purity (n = 7). Initial preclinical evaluation in rodent and nonhuman primate PET imaging studies revealed high initial brain uptake (peak rodent SUV = 2.5 @ 3 min postinjection; peak nonhuman primate SUV = 1.9 @ 5 min postinjection) followed by washout. Brain uptake was highest in thalamus, striatum, cortex, and cerebellum, areas known to be rich in GSK-3. These results make the arylindolemaleimide skeleton our lead scaffold for developing a PET radiotracer for quantification of GSK-3 density in vivo and ultimately translating it into clinical use.