Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR 2 ) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR 2 -targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR 2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity ( K i mGluR 2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [ 3 H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR 2 -rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR 2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [ 11 C]AZ12559322 ( 6a ) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR 2 PAMs with improved brain exposure.