DESIGN OF CLASS-SPECIFIC HDAC IMAGING PROBES FOR POSITRON EMISSION TOMOGRAPHY PROJECT SUMMARY A number of enzyme catalyzed processes have been identified which modify the DNA molecule and its associated chromatin. These epigenetic processes modulate gene expression. The association of epigenetic dysfunction with human disease has grown out of detailed molecular and chemical biology at the cellular and sub-cellular level. In some cases, these associations have led to new therapeutics agents, which can modulate epigenetic processes and potentially "rescue" the epigenetic status in diseased tissue. Despite the increasing link between epigenetic status at a molecular level and human disease and treatment, there are a surprisingly limited number of tools that allow researchers to directly probe epigenetic processes in vivo. New technologies for human molecular imaging that can report on enzymes which catalyze epigenetic transformations will revolutionize our ability to translate basic research to human therapy. To address this critical need, we aim to develop radiotracers for positron emission tomography (PET) that can provide molecular-level epigenetic information. While we will ultimately develop a series of radiotracers for a number of epigenetic targets, here we propose studies that will lead to an in vivo imaging agent relevant across many human diseases including, among others, cancer, central nervous system disorders, heart disease, and inflammation. Specifically, we will systematically develop and optimize a PET radiotracer for imaging class-I histone deacetylases (HDACs). We will accomplish this goal by: 1) developing and applying a distinct iterative refinement model to identifying class-specific HDAC inhibitors that, by design, contain a functional group suitable for PET radioisotope incorporation and which meet certain physiochemical criteria;2) Labeling appropriate precursor compounds and evaluating their in vivo imaging potential in detail in rodents;and 3) Optimizing top radiotracer candidates, performing non-human primate imaging, and assessing their potential for translation to humans. A key feature of this proposal is a research strategy that can be easily adapted to address other classes of HDAC agents and other epigenetic targets. The outcome of this research will be a new technology for imaging epigenetic processes in vivo that can be used in both preclinical research and human studies.

Public Health Relevance

DESIGN OF CLASS-SPECIFIC HDAC IMAGING PROBES FOR POSITRON EMISSION TOMOGRAPHY PROJECT NARRATIVE Evidence that environmental factors play a key role in regulating gene expression has introduced a new perspective on the relationships between gene expression and disease. In this grant application, we propose to develop a new in vivo imaging technology that will allow researchers to directly probe histone deacetylase (HDAC), a key enzyme regulating gene expression that has been the target of research related to developing new therapies for cancer, central nervous system disorders, heart disease, and inflammation. To accomplish this, we will select and synthesize small-molecule HDAC inhibitors that can be labeled with isotopes for use in positron emission tomography imaging and evaluate the ability of these probes to quantify HDAC expression level and activity using animal models. These tools will be use to accelerate epigenetic research and will ultimately be translated to human PET imaging and clinicians for diagnosing disease and monitoring treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030321-03
Application #
8267687
Study Section
Special Emphasis Panel (ZRG1-GGG-A (50))
Program Officer
Satterlee, John S
Project Start
2010-09-15
Project End
2015-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
3
Fiscal Year
2012
Total Cost
$436,769
Indirect Cost
$62,920
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Kim, Sung Won; Hooker, Jacob M; Otto, Nicola et al. (2013) Whole-body pharmacokinetics of HDAC inhibitor drugs, butyric acid, valproic acid and 4-phenylbutyric acid measured with carbon-11 labeled analogs by PET. Nucl Med Biol 40:912-8
Schroeder, Frederick A; Lewis, Michael C; Fass, Daniel M et al. (2013) A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests. PLoS One 8:e71323
Seo, Young Jun; Muench, Lisa; Reid, Alicia et al. (2013) Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain. Bioorg Med Chem Lett 23:6700-5
Fass, Daniel M; Reis, Surya A; Ghosh, Balaram et al. (2013) Crebinostat: a novel cognitive enhancer that inhibits histone deacetylase activity and modulates chromatin-mediated neuroplasticity. Neuropharmacology 64:81-96

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