In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs

Changning Wang, Frederick A Schroeder, Hsiao-Ying Wey, Ronald Borra, Florence F Wagner, Surya Reis, Sung Won Kim, Edward B Holson, Stephen J Haggarty, Jacob M Hooker

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Abstract

Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [(11)C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [(11)C]6 for human epigenetic imaging.

Original languageEnglish
Pages (from-to)7999-8009
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number19
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Animals
  • Autoradiography
  • Brain
  • Dose-Response Relationship, Drug
  • Epigenomics
  • Histone Deacetylase Inhibitors
  • Histone Deacetylases
  • Humans
  • Kidney
  • Male
  • Myocardium
  • Papio
  • Positron-Emission Tomography
  • Rats
  • Rats, Sprague-Dawley
  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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