# In vivo Probe for ionotropic glutamate signaling system: AMPA receptors

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $1

## Abstract

Project Summary: We will develop the first subtype-selective positron emission tomography (PET) probe for α-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) in the ionotropic glutamate system.
 Dysfunction of AMPAR is implicated in the physiopathology of neurological diseases such as schizophrenia,
depression, epilepsy and Parkinson’s disease. Pharmacological modulation of AMPAR prevents excessive neuronal
activation, representing an attractive therapeutic approach. As a non-invasive chemical probe, PET is capable of
quantifying biochemical processes in vivo, and a suitable AMPAR PET probe would substantially improve our
understanding of AMPAR-based ionotropic glutamate signaling under normal and disease conditions otherwise
inaccessible by ex vivo (destructive) analysis. To date, no successful examples have been demonstrated to image
AMPAR, representing a significant deficiency of our ability to study this target in vivo. Therefore, we propose to
develop a PET probe that can fill this void, as the first translational AMPAR imaging tool.
 As pan AMPAR antagonists are often accompanied by debilitating adverse effects and have a very narrow
therapeutic dosing window, one recent advance focuses on subtype-selective AMPAR antagonists via modulating
transmembrane AMPA regulatory proteins (TARPs). The PI and his team have pioneered the development of the first
subtype-selective AMPAR PET probe targeting AMPAR subunit TARP ɣ8, [11C]JNJ-486 at MGH. [11C]JNJ-486
showed high in vitro specific binding and target selectivity towards AMPAR TARP ɣ8 subunit, but was discontinued
due to low brain penetration. Through our established HEK293 cell-based Ca2+ flux fluorescent assay, we identified a
second generation chemical lead. This compound showed high potency and high subtype selectivity. An 11C-
isotopologue was then synthesized and preliminary PET studies confirmed that we have overcome the two major
obstacles for AMPAR probe development, namely: 1) reasonable brain uptake and 2) regional-specific uptake.
Though this lead is a promising template for the development of new TARP ɣ8-targeted in vivo chemical tool, PET
probes with improved potency & selectivity, and increased binding potentials (Bmax/Kd) are needed for optimal imaging
and quantification of subtype-selective AMPAR in translational cross-species imaging studies.
 In this proposal, we will design and prepare a series of carefully chosen subtype-selective AMPAR inhibitors, label
top candidates with 11C or 18F, and evaluate their ability to quantify AMPAR during drug challenges in rodents and
nonhuman primates. The impact of this work is not only to develop the first potent and selective AMPAR PET probe
for the study of disease-related biological processes, but also ultimately, to prepare this in vivo tool for potential clinical
translation and monitor target response of AMPAR therapeutic agents in the brain.
Relevance: This proposal has the potential to improve public health and h...

## Key facts

- **NIH application ID:** 10134117
- **Project number:** 5R01MH120197-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Steven H Liang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2019-06-21 → 2022-03-01

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134117

## Citation

> US National Institutes of Health, RePORTER application 10134117, In vivo Probe for ionotropic glutamate signaling system: AMPA receptors (5R01MH120197-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10134117. Licensed CC0.

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