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 #
3R01DA030321-04S1
Application #
8659008
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
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$9,180
Indirect Cost
$680
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Schroeder, Frederick A; Gilbert, Tonya M; Feng, Ningping et al. (2017) Expression of HDAC2 but Not HDAC1 Transcript Is Reduced in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia. ACS Chem Neurosci 8:662-668
Wey, Hsiao-Ying; Gilbert, Tonya M; Zürcher, Nicole R et al. (2016) Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci Transl Med 8:351ra106
Placzek, Michael S; Zhao, Wenjun; Wey, Hsiao-Ying et al. (2016) PET Neurochemical Imaging Modes. Semin Nucl Med 46:20-7
Ghosh, Balaram; Zhao, Wen-Ning; Reis, Surya A et al. (2016) Dissecting structure-activity-relationships of crebinostat: Brain penetrant HDAC inhibitors for neuroepigenetic regulation. Bioorg Med Chem Lett 26:1265-1271
Strebl, Martin G; Wang, Changning; Schroeder, Frederick A et al. (2016) Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance. ACS Chem Neurosci 7:528-33
Wey, Hsiao-Ying; Wang, Changning; Schroeder, Frederick A et al. (2015) Kinetic Analysis and Quantification of [¹¹C]Martinostat for in Vivo HDAC Imaging of the Brain. ACS Chem Neurosci 6:708-15
Wang, Changning; Schroeder, Frederick A; Wey, Hsiao-Ying et al. (2014) In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs. J Med Chem 57:7999-8009
Schroeder, F A; Wang, C; Van de Bittner, G C et al. (2014) PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat. ACS Chem Neurosci 5:1055-62
Seo, Young Jun; Kang, Yeona; Muench, Lisa et al. (2014) Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors. ACS Chem Neurosci 5:588-96
Wang, C; Schroeder, F A; Hooker, J M (2014) Visualizing epigenetics: current advances and advantages in HDAC PET imaging techniques. Neuroscience 264:186-97

Showing the most recent 10 out of 21 publications