Open AccessDevelopment of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance
Author(s) -
Martin G. Strebl,
Changning Wang,
Frederick A. Schroeder,
Michael S. Placzek,
Hsiao Ying Wey,
Genevieve C. Van de Bittner,
Ramesh Neelamegam,
Jacob M. Hooker
Publication year - 2015
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/acschemneuro.5b00297
Subject(s) - penetrance , histone deacetylase , neuroscience , epigenetics , positron emission tomography , human brain , pet imaging , medicine , psychology , pharmacology , biology , histone , genetics , phenotype , gene
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.