# Novel PET Tracers for Imaging Monoacylglycerol Lipase in Endocannabinoid Signaling

> **NIH NIH R33** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $17,526

## Abstract

Project Summary: The goal of the Early Career Award in Chemistry of Drug Abuse and Addiction (ECHEM)
(R21/R33) is to help applicant establish an independent and highly-competitive chemistry research program applied
to drug abuse and addiction, with a major focus of developing radiopharmaceuticals for PET imaging study of
monoacylglycerol lipase (MAGL) in the endocannabinoid signaling system.
 MAGL is the principle enzyme for metabolizing endogenous cannabinoid ligand: 2-arachidonylglycerol (2-AG).
Blockade of MAGL increases 2-AG levels, resulting in anti-nociceptive, anxiolytic and anti-emetic responses, and
has emerged as a therapeutic strategy to treat drug addiction and substance-use disorders (SUDs). Human genetic
studies have identified the link between MAGL mutations and increased risk for addiction. Abnormal MAGL
expression has been detected in the post-mortem brain of alcoholic subjects. However, these results discovered via
ex vivo (destructive) analysis cannot provide a direct and real-time correlation between MAGL activity and human
disease stages, particularly for tissues such as the brain. In this context, a PET radiotracer can fill this void and
provide a noninvasive tool for quantifying MAGL activity and possible aberrant eCB function in drug abuse and
addiction. However, the foremost barrier holding back PET applications for this purpose is the scarcity of
radiotracers targeting MAGL, representing a significant deficiency in our understanding of this enzyme.
 The first brain penetrant MAGL radiotracer, [11C]SAR127303 recently developed by the PI and others, showed
saturable binding but this compound also binds a second 2-AG degrading enzyme, ABHD6, thereby undermining
the specific binding in the brain. To overcome this selectivity problem, we will utilize a novel proteomic technology,
activity based protein profiling (ABPP) to perform target selectivity screening based on an array of novel MAGL
inhibitors developed in house. An azetidine carbamate exhibits >500-fold selectivity to MAGL over FAAH, CB1 and
CB2 receptors, and >30-fold MAGL over ABHD6. Preliminary studies indicate the 11C-labeled azetidine crosses the
blood brain barrier in rat and nonhuman primate (NHP), and shows high specific binding. Although it is not clear if
this radiotracer will be satisfactory for human use, it shows promise as a first generation of selective MAGL
radiotracers. In addition to further evaluation of this tracer, we will use this scaffold to concurrently prepare a series
of carefully chosen MAGL tracers with further improved selectivity, and evaluate their ability to quantify MAGL
activity using rodents and NHPs. The impact of this work is not only to develop the first potent and selective MAGL
neurotracer for basic eCB research, but also ultimately to progress this imaging tool for translational human imaging
studies and investigate underlying mechanisms of MAGL-linked diseases including SUDs.
Relevance: This proposal has the potential to impro...

## Key facts

- **NIH application ID:** 10407153
- **Project number:** 3R33DA043507-04S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Steven H Liang
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $17,526
- **Award type:** 3
- **Project period:** 2017-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407153

## Citation

> US National Institutes of Health, RePORTER application 10407153, Novel PET Tracers for Imaging Monoacylglycerol Lipase in Endocannabinoid Signaling (3R33DA043507-04S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10407153. Licensed CC0.

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