AMPAR ligand discovery for Alzheimer's disease

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Project Summary. AMPA receptors (AMPARs) are the principle transducers of fast glutamatergic neurotransmission throughout the central nervous system (CNS), where they control the strength of excitatory synapses and modulate long-term potentiation (LTP) - a fundamental mechanism of learning and memory function. AMPAR dysfunction has been implicated in a variety of neurodegenerative diseases, including Alzheimer’s disease (AD). Therefore pharmacological modulation of AMPAR represents an attractive therapeutic approach. Positron emission tomograohy (PET) is capable of quantifying biochemical processes in vivo, and a suitable AMPAR ligand would substantially improve our understanding of AMPAR-mediated ionotropic glutamate signaling under different pathophysiological AD conditions, otherwise inaccessible by ex vivo (destructive) analysis. Quantification of AMPAR in living brain by PET would provide the assessment of distribution, target engagement and dose occupancy of new AMPAR-targeted neurotherapeutics. To date, no successful examples have been demonstrated to image GluA2-specific AMPAR 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 AMPAR GluA2-specific ligands, including [11C]AMPA-1905 (developed by the PI in 2020). However, this ligand was discontinued due to marginal binding specificity in vivo. In our 2nd generation, we identified a lead molecule, AMPA-2076, which showed high binding affinity and excellent selectivity over all other iGlu receptors. An 18F-isotopologue of AMPA-2076 was synthesized and preliminary PET imaging studies confirmed that we have overcome two major obstacles for GluA2-specific AMPAR ligand development by achieving: 1) substantially-improved in vivo stability in the brain and 2) high target specificity. Though AMPA-2076 is a promising lead molecule for the development of new GluA2-targeted AMPAR ligands, further optimization for improved binding specificity with proper brain kinetics are sought for translational cross-species imaging studies to achieve optimal AMPAR (GluA2 subunit) quantification in the living brain for drug discovery and clinical translation for AD patients. On the basis that AMPA-2076 serves a validated lead for medicinal chemistry optimization, as specific goals, we will design and prepare a focused library of GluA2-specific AMPAR modulators amenable for labeling with 11C or 18F, and evaluate their ability to quantify AMPAR activity and changes during drug challenge in rodents and nonhuman primates, as well as autoradiography and biological validation in postmortem human brain tissues. The impact of this work is not only to develop the first successful high-affinity and selective AMPAR 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.