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 (mGluR₂) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR₂-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR₂ positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K_i mGluR₂ = 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, [³H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR₂-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR₂ PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [¹¹C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR₂ PAMs with improved brain exposure.