Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance

ACS Chem Neurosci. 2016 May 18;7(5):528-33. doi: 10.1021/acschemneuro.5b00297. Epub 2015 Dec 21.


Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [(11)C]Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [(11)C]Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and nonhuman primates. The study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life.

Keywords: blood-brain barrier; brain penetrance; epigenetics; fluorine; histone deacetylase; positron emission tomography.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adamantane / analogs & derivatives*
  • Adamantane / chemistry
  • Adamantane / metabolism
  • Animals
  • Brain / diagnostic imaging*
  • Brain / metabolism*
  • Female
  • Histone Deacetylases / metabolism*
  • Hydroxamic Acids / chemistry
  • Hydroxamic Acids / metabolism*
  • Male
  • Papio
  • Positron-Emission Tomography / methods
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Rats, Sprague-Dawley


  • Hydroxamic Acids
  • Radiopharmaceuticals
  • martinostat
  • Histone Deacetylases
  • Adamantane