# Epigenetic Radiotracers for PET Imaging: Isoform-SelectiveHDAC Probes

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $467,447

## Abstract

Project Summary
The development of isoform-selective histone deacetylase (HDAC) radiotracers will fill critical knowledge gaps
that exist in our understanding of HDAC function in the human brain. HDAC6 is primary among the isoforms of
HDAC that, to date, have exhibited strong therapeutic potential. Compelling preclinical evidence supports
HDAC6 inhibition for the treatment of depression and neurodegenerative diseases and translational tools such
as a positron emission tomography radiotracer targeting HDAC6 will allow us to assess the relevance of
preclinical findings in the human brain. HDAC6 acts not by removing acetyl groups from histones as its name
might suggest, but instead by regulating the acetylation state of several non-histone proteins including α-
tubulin, cortactin, tau, HSP90 and β-catenin. Inhibitors that selectively engage HDAC6 over the other ten
isoforms of HDAC have been developed by our team and by others in the field and provide the foundation for
PET radiotracer development. Using known HDAC6 inhibitor scaffolds, we will design and synthesize a library
of HDAC6 inhibitors that can be readily labeled with a positron-emitting isotope (carbon-11 or fluorine-18). The
library will undergo rigorous physiochemical and biochemical profiling including assays that evaluate HDAC-
isoform selectivity and efficacy in cultured human neurons and that predict blood-brain barrier penetration.
Compounds prioritized through these assays will be radiolabeled and evaluated in rodents for brain uptake,
pharmacokinetics and specific (saturable) binding. Promising in vivo imaging results will be validated using
HDAC6 knock-out mouse imaging. Finally to set the stage for translation to human HDAC6 imaging (which our
team has accomplished for class-I HDAC imaging), we will evaluate priority compounds in non-human
primates to determine regional brain binding using full metabolite-corrected arterial blood input function
correction and kinetic modeling. By the end of the grant project period, our team will be poised to measure the
density-distribution of HDAC6 in the human brain over the course of natural heterogeneity (e.g. age and sex
differences) and in patients with HDAC6-implicated brain disorders.

## Key facts

- **NIH application ID:** 9915983
- **Project number:** 5R01NS099250-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** STEPHEN J HAGGARTY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,447
- **Award type:** 5
- **Project period:** 2017-07-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915983

## Citation

> US National Institutes of Health, RePORTER application 9915983, Epigenetic Radiotracers for PET Imaging: Isoform-SelectiveHDAC Probes (5R01NS099250-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9915983. Licensed CC0.

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