# MAGL PET tracer-guided prognosis and neuroprotective therapy for Alzheimer's disease

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $165,552

## Abstract

Project Summary
 Monoacylglycerol lipase (MAGL) is the principle enzyme for metabolizing the endogenous cannabinoid ligand: 2-
arachidonylglycerol (2-AG). Inhibition of MAGL, not only increases 2-AG levels, resulting in activation of the
endocannabinoid system (eCB), but also reduces levels of arachidonic acid (AA), a pain and inflammation-inducing
prostaglandin precursor. This unique synergetic effect provides protection against neuroinflammation and
neurodegenerative diseases. Genetic ablation of MAGL has also resulted in an attenuation of neuroinflammation, for
example, a substantial reduction of amyloid plaques in transgenic mouse model of Alzheimer’s disease (AD). In
autopsy brains of Alzheimer’s patients, MAGL levels in nucleus basalis are 600-800% higher than that of normal brain,
and showed a positive correlation (R = 0.8) between enzyme expression levels and AD Braak stage (I-VI).
 In the past, remarkable advances have been made in the understanding of MAGL and its modulation at the
molecular level in neurodegenerative diseases via ex vivo (destructive) analysis, which, by definition, cannot be
directly translated to most human tissues in vivo. In this context, positron emission tomography (PET) is a noninvasive
molecular imaging tool that can provide such information via targeted radioactive molecules (radiotracers) with
exquisite sensitivity, which will be highly advantageous in monitoring disease progression and treatment response.
The radiotracer [11C]SAR127303 (abbreviated as [11C]SAR127), developed by the PI, can fill this void and provide
a quantitative tool for measuring MAGL activity and possible aberrant eCB function in AD. Our preliminary studies
show that [11C]SAR127 is a specific and brain penetrant PET radiotracer that is consistent with the distribution of
MAGL in the brain. In this application, we aim to evaluate [11C]SAR127 for its ability to track MAGL changes in vivo
to monitor disease progression in transgenic AD mouse models, evaluate target engagement and assess treatment
response to MAGL-related pharmacotherapies.
 This work will represent the first PET biomarker study measuring changes of a potentially disease-modifying
enzyme MAGL in the AD progression and treatment. We expect that this proposed work will not only help us to
differentiate symptomatic from true neuroprotective response via MAGL inhibition, but also contribute to the
development of MAGL-based therapeutic interventions to improve quality of life of AD patients.
Relevance: This proposal has the potential to improve public health and help patients suffering from Alzheimer’s
disease through the discovery of novel neurotherapeutics using MAGL PET ligands.

## Key facts

- **NIH application ID:** 10001417
- **Project number:** 5R03AG063290-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Steven H Liang
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $165,552
- **Award type:** 5
- **Project period:** 2019-09-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001417

## Citation

> US National Institutes of Health, RePORTER application 10001417, MAGL PET tracer-guided prognosis and neuroprotective therapy for Alzheimer's disease (5R03AG063290-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10001417. Licensed CC0.

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