Abstract
Dysfunction of GSK3 is implicated in the etiology of many brain, inflammatory, cardiac diseases, and cancer. PET imaging would enable in vivo detection and quantification of GSK3 and can impact the choice of therapy, allow non-invasive monitoring of disease progression and treatment effects. In this report, the synthesis and evaluation of a high affinity GSK3 ligand, [(11)C]2-(cyclopropanecarboxamido)-N-(4-methoxypyridin-3-yl)isonicotinamide, ([(11)C]CMP, (3), (IC(50) = 3.4 nM, LogP = 1.1) is described. [(11)C]CMP was synthesized in 25 ± 5% yield by radiomethylating the corresponding phenolate using [(11)C]CH(3)I. The radioligand exhibited modest uptake in U251 human glioblastoma cell lines with ∼50% specific binding. MicroPET studies in rats indicated negligible blood-brain barrier (BBB) penetration of [(11)C]CMP, despite its high affinity and suitable logP value for BBB penetration. However, administration of cyclosporine prior to [(11)C]CMP injection showed significant improvement in brain radioactivity uptake and the tracer binding. This finding indicates that [(11)C]CMP might be a P-gp efflux substrate and therefore has some limitations for routine in vivo PET evaluations in brain.