# Development of GCPII inhibitors for the treatment of age-related cognitive disorders

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2024 · $784,969

## Abstract

Project Summary
The goal of this research proposal is to develop brain-penetrant inhibitors of glutamate carboxypeptidase II
(GCPII) as a new therapeutic strategy to improve cognition and reduce risk of late-onset Alzheimer's Disease
(AD). GCPII (EC 3.4.17.21) is a membrane-bound zinc metallopeptidase that cleaves the C-terminal
glutamate from N-acetylaspartylglutamate (NAAG) producing N-acetylaspartate and glutamate. NAAG is
known to act as an endogenous agonist at metabotropic glutamate receptor type 3 (mGluR3) and we have
recently found that NAAG can enhance memory-related neuronal firing in monkeys through stimulation of
Gi/Go-mediated regulation of postsynaptic cAMP-PKA-calcium signaling. Therefore, GCPII inhibition may
offer a new therapeutic approach to the cognitive impairments by increasing extracellular NAAG levels and
controlling cAMP-PKA-calcium signaling dysregulated in the aging brain. In the absence of mGluR3-selective
agonists and positive allosteric modulators, this approach is particularly attractive as a number of structurally
diverse and potent GCPII inhibitors have been developed and preclinically evaluated in a variety of
neurological disorders with a robust efficacy and an excellent side effect profile. Indeed, our preliminary data
show cognitive enhancement upon treatment with 2-MPPA, a clinically tested GCPII inhibitor, in aged rats
and monkeys. To date, however, efforts on clinical translation of GCPII inhibitors have been substantially
limited despite the significant therapeutic potential. This prompted us to propose a broad range of
pharmacological approaches to the development of brain-penetrant GCPII inhibitors. We are poised to seize
this therapeutic opportunity for the treatment of age-related cognitive disorders by executing the following
three Specific Aims: (Aim 1) Design and synthesis of GCPII inhibitors and their prodrugs; (Aim 2) Evaluate
the pharmacokinetic (PK) profile of GCPII inhibitors in rats and monkeys; (Aim 3) Assess the effects GCPII
inhibitors on cognitive function in aged rats and monkeys. The successful execution of this project will lead
to a novel therapeutic strategy with greater feasibility for clinical translation to address the main healthcare
needs of the growing elderly population.

## Key facts

- **NIH application ID:** 10863984
- **Project number:** 5R01AG068130-05
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** AMY F.T. ARNSTEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $784,969
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10863984

## Citation

> US National Institutes of Health, RePORTER application 10863984, Development of GCPII inhibitors for the treatment of age-related cognitive disorders (5R01AG068130-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10863984. Licensed CC0.

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