# Subtype-selective NMDA ligands for Alzheimer's Disease

> **NIH NIH R01** · EMORY UNIVERSITY · 2023 · $780,998

## Abstract

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 potent...

## Key facts

- **NIH application ID:** 10593906
- **Project number:** 5R01AG075444-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Steven H Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $780,998
- **Award type:** 5
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10593906

## Citation

> US National Institutes of Health, RePORTER application 10593906, Subtype-selective NMDA ligands for Alzheimer's Disease (5R01AG075444-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10593906. Licensed CC0.

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