# PET ligand development for mGlu2 based on negative allosteric modulators

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $625,674

## Abstract

Project Summary: The goal of this project is to develop the first negative allosteric modulator (NAM)-based positron
emission tomography (PET) ligand for metabotropic glutamate receptor subtype 2 (mGlu2) based on negative
allosteric modulation as imaging biomarker for drug discovery.
 The physiological function of mGlu2 is to negatively regulate endogenous glutamate release and protect neurons
against excitotoxicity. Continuous efforts to modulate mGlu2 represent a broad pharmacological approach for the
treatment of CNS disorders, including drug addiction, depression, schizophrenia, Parkinson’s disease and Alzheimer’s
disease. As a non-invasive imaging technology, PET is capable of quantifying biochemical processes in vivo, and a
suitable mGlu2 PET ligand would substantially improve our understanding of mGlu2-based glutamatergic signaling
under normal and disease conditions otherwise inaccessible by ex vivo (destructive) analysis. Furthermore,
quantification of mGlu2 by PET would provide the assessment of distribution, target engagement and dose occupancy
of mGlu2-targeted new neurotherapeutics. To date there is no successful examples have been demonstrated to image
mGlu2, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to develop
a PET ligand for mGlu2 that will overcome the two major shortcomings of previous PET ligands (low brain uptake and
limited target specificity) and be the first mGlu2 imaging agent for drug discovery and clinical translation.
 The first NAM-based mGlu2 ligand, [11C]QCA, was recently developed by the PI at MGH. [11C]QCA showed
excellent in vitro specific binding and target selectivity towards mGlu2, but was discontinued due to low brain
penetration. In our second generation mGlu2 NAMs, we identify a lead pyridine compound with high potency and
selectivity towards mGlu2. A 11C-isotopolgue of this lead showed reasonable brain uptake (1.1 SUV) and target
engagement in pretreatment studies (~60% blockade). Though our lead candidate is a promising lead for the
development of new mGlu2-targeted target engagement tool, PET ligands with higher brain penetration, improved
potency and selectivity, increased specific binding ratios are needed for optimal imaging and quantification of mGlu2.
 In this proposal, we will design and prepare a series of carefully chosen mGlu2 NAMs, radiolabel top candidates
with 11C or 18F, and evaluate their ability to quantify mGlu2 activity and changes during drug challenges in rodents and
nonhuman primates. The impact of this work is not only to develop the first potent and selective mGlu2 PET NAM
ligand for drug discovery, but also ultimately, to prepare this imaging tool for potential clinical translation and monitor
direct effect of mGlu2 therapeutic agents in human brain. The target validation and occupancy for efficacious mGlu2-
related treatment can also be determined and quantified by the mGlu2 PET ligands in this work.
Relevance: This pr...

## Key facts

- **NIH application ID:** 9897594
- **Project number:** 5R01MH117125-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Steven H Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $625,674
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897594

## Citation

> US National Institutes of Health, RePORTER application 9897594, PET ligand development for mGlu2 based on negative allosteric modulators (5R01MH117125-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9897594. Licensed CC0.

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