Subtype-Selective Metabotropic Glutamate Receptor PET Ligands

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Project Summary. The physiological function of mGluR2 is to negatively regulate endogenous glutamate release and protect neurons against excitotoxicity. Therefore pharmacological modulation of mGluR2 represents an attractive therapeutic approach for the treatment of neurological disorders and neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and related dementias (ADRD). Positron emission tomography (PET) is capable of quantifying biochemical processes in vivo, and a suitable mGluR2 ligand would substantially improve our understanding of mGluR2-mediated signaling pathway under different pathophysiological CNS disorders, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of mGluR2 in living brain by PET would provide the assessment of distribution, target engagement and pharmacodynamic response of novel mGluR2-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image mGluR2 in humans for drug discovery and clinical use, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop a novel PET ligand that can fill this void, as the first translational imaging tool. We are the first groups to develop negative allosteric modulator (NAM) based mGluR2 ligands in cross-species PET studies, including [11C]QCA. However, this ligand was discontinued due to low brain penetration and marginal binding specificity in vivo. As our next generation, we identified a lead molecule, MG2-2112, which showed high binding affinity and excellent selectivity. Our preliminary evaluation confirmed that we have overcome the two major obstacles for mGluR2 ligand development by achieving: 1) substantially-improved binding affinity, representing the best compound to date; and 2) high brain permeability and target specificity (characteristic high uptake in mGluR2- rich striatum and low in mGluR2-poor thalamus/pons). Though MG2-2112 is a promising lead, we are not clear if it is satisfactory for PET quantification in cross-species study for drug discovery and clinical translation. Thus, we will advance MG2-2112 as a benchmark and concurrently prepare a series of mGluR2-specific PET ligands. Further optimization for improved binding specificity and proper brain kinetics, as well as proof-of-concept validations on human brain tissues, are sought to identify optimal mGluR2 ligands and support target engagement study and efficacy measurement in drug discovery. The impact of this work is not only to develop the first successful highly-specific mGluR2 PET ligand for the study of neurological disorders and neurodegenerative diseases-related biological processes, but also ultimately, via PET imaging validation in higher species, to advance this ligand for potential clinical translation and monitor target response and safety margins of novel neurotherapeutics for neurodegenerative diseases, including AD.