# Development of PET imaging probes for metabolic glutamate receptor 3 (mGLuR3)

> **NIH NIH K25** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $150,726

## Abstract

Project Summary/Abstract: The goal of this career development proposal is to develop a sensitive PET
probe for in vivo imaging of mGluR3, which might provide valuable insight to elucidate key biochemical
mechanisms in the pathogenesis of Alzheimer's disease (AD) while providing me an excellent opportunity to
grow as an independent scientist. Glutamate is the most abundant excitatory neurotransmitter in the vertebrate
central nervous system (CNS), which mediates more than 50% of all synapses. The glutamatergic
neurotransmission plays important roles in various brain functions, including motor control, learning and
memory, cognition, and neural development. AD is a devastating neurodegenerative disorder that triggers a
complex cascade leading to synaptic alterations, neurotransmitter deficiencies, and cognitive failure. Treatment
of AD is the largest unmet need in neurology. Only four drugs (three cholinesterase inhibitors and memantine)
are approved for the treatment of AD, and none of them has shown significant disease-modifying activity.
 Our understanding of the etiology and pathobiology of AD-related neurodegeneration remains limited. The
studies show that mGluR3 is increasingly linked to age-related cognitive disorders, which are expected to
stimulate the production of TGF-β, rescue memory deficits and to stimulate the activity of α-secretase. It is the
activation of mGluR3 not mGluR2 to induce neuroprotection, while activation of mGluR2 may lead
neurotoxicity. Presently, PET imaging has an increasing role in the diagnosis of AD. However, the potential of
PET strongly depends on the availability of suitable PET radiotracers. Even, as a very promising target for AD
and other CNS disorders, there is no PET ligand for imaging of mGluR3. There is tremendous need for specific
and selective imaging ligands to verify the drug targets and to investigate mGluR3 in physiological and
pathological processes. The potential impact of an mGluR3 PET tracer will be major to investigate underlying
pathology of AD and enhance drug development.
 Here we propose to develop mGluR3-selective PET imaging ligands based on the allosteric modulators,
with aims to evaluate the reported lead compounds, to carry out SAR study, to optimize the lead with respect
to affinity, selectivity, metabolic stability and other pharmacological properties, to radiolabel the optimized
ligands, and to demonstrate proof of concept in animal models. Specifically, we will develop fluorine-18 labeled
PET tracers with optimized pharmacological properties for selectively imaging mGluR3 in vivo. We will study
the expression, distribution and function of mGluR3 in normal and pathological conditions also using AD-
mouse models. From the training perspective, the proposed work will allow me to extend my expertise in
medicinal and organic chemistry to the development of PET imaging probes and characterize them in
preclinical studies for neurological diseases, which could lead to improved diagnosis,...

## Key facts

- **NIH application ID:** 9895608
- **Project number:** 5K25AG061282-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JUNFENG WANG
- **Activity code:** K25 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $150,726
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895608

## Citation

> US National Institutes of Health, RePORTER application 9895608, Development of PET imaging probes for metabolic glutamate receptor 3 (mGLuR3) (5K25AG061282-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9895608. Licensed CC0.

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