Subtype-selective NMDA ligands for Alzheimer's Disease

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Project Summary: Dysfunction of GluN2B subunit in the N-Methyl-D-aspartic acid receptor (NMDAR) is implicated in the physiopathology of neurodegenerative diseases such as Alzheimer’s disease (AD) and related dementia. Pharmacological modulation of GluN2B subunit regulates synaptic plasticity and excitation, representing an attractive therapeutic approach. PET is capable of quantifying biochemical processes in vivo, and a suitable GluN2B ligand would substantially improve our understanding of GluN2B-based ionotropic glutamate signaling under physiopathological conditions otherwise inaccessible by ex vivo (destructive) analysis. Quantification of GluN2B in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new GluN2B-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluN2B for human 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 overcome major drawbacks of previous attempts (low brain permeability / limited target specificity / high lipophilicity), as the first translational imaging tool for drug discovery. Our first generation GluN2B-targeted ligand, [18F]N2B-0518 showed excellent potency, target selectivity and high specific binding, but was discontinued due to low brain penetration and fast metabolism in vivo. In our next generation, we successfully identified a lead molecule, N2B-94, which showed high potency and selectivity towards GluN2B over all other NMDAR subunits. An 11C-isotopologue of N2B-94 was synthesized and preliminary PET imaging studies confirmed that we have overcome the major obstacles for GluN2B ligand development by achieving: 1) high brain uptake; 2) high target specificity, as well as well-improved in vivo stability. Though N2B-94 is a promising lead molecule, PET ligands with higher brain penetration, improved potency and selectivity with proper brain kinetics are sought for translational cross-species imaging studies to achieve optimal quantification of GluN2B in the living brain. On the basis that N2B-94 serves a validated hit for medicinal chemistry optimization, as specific goals, we will design and prepare a series of GluN2B modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify GluN2B activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem brain tissues from higher species. The impact of this work is not only to develop the first potent and selective GluN2B PET ligand for the study of neurodegenerative disease- 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 of novel neurotherapeutics for neurodegenerative diseases, including AD. Relevance: This proposal has the potential to improve public health and help patients suffering from neurodegenerative diseases, including AD, through the discovery of neurotherapeutics using GluN2B-selective NMDAR PET ligands.