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

Martin G. Strebl, Changning Wang, Frederick A. Schroeder, Michael S. Placzek, Hsiao Ying Wey, Genevieve C. Van De Bittner, Ramesh Neelamegam, Jacob M. Hooker

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

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, [11C]Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [11C]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.

Original languageEnglish (US)
Pages (from-to)528-533
Number of pages6
JournalACS Chemical Neuroscience
Volume7
Issue number5
DOIs
StatePublished - May 18 2016
Externally publishedYes

Keywords

  • blood-brain barrier
  • brain penetrance
  • epigenetics
  • fluorine
  • histone deacetylase
  • positron emission tomography

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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