Glycogen Synthase Kinase-3 Maleimide Inhibitors As Potential PET-Tracers for Imaging Alzheimer's Disease:...

Herein we present the evaluation of ¹¹C-labeled-maleimides as radiotracers for positron emission tomography imaging of GSK-3 associated with Alzheimer's disease (AD). 3-Acetyl-4-(1-[¹¹C]-methyl-1H-indol-3-yl)[1H]pyrrole-2,5-dione ([¹¹C]-2) was obtained by direct methylation using [¹¹C]-CH₃I and Cs₂CO₃ in DMF with a 31 ± 4% radiochemical yield and a radiochemical purity of 97.7 ± 0.8%. [¹¹C]-2 was stable both in its final formulation and in human plasma for 120 min and had a plasma protein binding of 70 ± 1% and a LogD_7.4 value of 1.84 ± 0.04. [¹¹C]-2 ex vivo biodistributions in healthy animals demonstrated significant brain uptake and retention, showing its ability to penetrate the intact blood-brain barrier. In vivo PET imaging in mice bearing AD showed, with respect to normal animals, significant differences in uptake in the hypothalamus, the striatum, and the amygdala and a significant increase in amygdala uptake in later stages of the pathology. These results are very promising, and further studies are being performed for a complete validation of this compound as novel tracer for AD.