# COX-2-Selective PET Imaging as an Onset Marker of Huntington's Disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $606,476

## Abstract

Project Summary
Huntington’s Disease (HD) is an autosomal dominant, neurodegenerative disease characterized by involuntary
movement dysfunction, and cognitive and psychiatric symptoms, ultimately resulting in death. Although
diagnostic testing is available for HD, there remains a critical need for an objective clinical marker to characterize
both disease onset and progression. In order to develop effective therapeutics to support early intervention and
prevent decline, we need to understand the early-stage biological changes in the living brain that occur at disease
conversion. Imaging with positron emission tomography (PET) facilitates in vivo longitudinal measurements of
molecular changes that manifest with evolving pathology. To date however, no PET ligands have been generated
to predict disease conversion or aid prognosis in HD. Recent studies have shown that glial cell activation can be
detected either at or just prior to the onset of symptoms in HD patients, evoking potential for the development of
such a ligand. In addition, there is emerging evidence from neurodegenerative disease models that microglia,
the brain’s resident immune cells, play an important role in some of the earliest pathological events, including
synaptic loss. Our preliminary data showing increased cyclooxygenase-2 (COX-2) protein in both HD patient and
HD mouse model brains (postmortem), suggest it holds promise as a novel clinical marker. Preclinical models
exhibit elevated COX-2 during periods of microglia-mediated synaptic elimination, an event early in the pathology
of many neurodegenerative diseases. In addition, we see COX-2 is increased specifically in the microglia of
disease-affected regions in human HD post-mortem brain tissue. The only way to truly understand the role that
COX-2 plays in HD is to examine its presence and dynamics in the human brain throughout the course of
disease. Therefore, we propose to develop a selective radiotracer for in vivo PET imaging to study COX-2
dysregulation in the living brain, and carry out ex vivo mechanistic studies of COX-2 function in microglia. We
will synthesize novel COX-2-selective ligands, optimized for affinity, target selectivity, high brain uptake, and
amenability to radiolabeling with carbon-11 or fluorine-18. These ligands will undergo rigorous physiochemical
and biochemical profiling, including assays that evaluate COX-2-isoform selectivity, and that predict blood-brain
barrier penetration. Lead compounds will be radiolabeled and evaluated with in vitro autoradiography using
human HD post-mortem brain tissue to evaluate specific and saturable binding. This will be followed by in vivo
imaging in rodents with PET to evaluate brain uptake, radiotracer kinetics, and radiometabolites. In parallel, we
will elucidate biochemical mechanisms of COX-2 in microglia in HD mouse models, and investigate the role
COX-2 plays in altering microglial function. By the end of the grant project period, our team will have the abili...

## Key facts

- **NIH application ID:** 10745948
- **Project number:** 5R01NS111168-05
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Jacob M. Hooker
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $606,476
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10745948

## Citation

> US National Institutes of Health, RePORTER application 10745948, COX-2-Selective PET Imaging as an Onset Marker of Huntington's Disease (5R01NS111168-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10745948. Licensed CC0.

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