title: Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance.
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, [(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.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.|Department of Chemistry and Chemical Biology, Harvard University , 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Strebl
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Changning
authors.initials: C
authors.lastname: Wang
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Schroeder
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.|Department of Psychiatry, McLean Imaging Center, McLean Hospital, Harvard Medical School , 115 Mill Street, Belmont, Massachusetts 02478, United States.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Placzek
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Hsiao-Ying
authors.initials: HY
authors.lastname: Wey
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Genevieve C
authors.initials: GC
authors.lastname: Van de Bittner
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Neelamegam
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School , 149 13th Street, Charlestown, Massachusetts 02129, United States.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D006655:Histone Deacetylases / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000378:metabolism; D017207:Rats, Sprague-Dawley
chemical_list: D006877:Hydroxamic Acids; D019275:Radiopharmaceuticals; C000605558:martinostat; D006655:Histone Deacetylases; D000218:Adamantane
keywords: blood-brain barrier; brain penetrance; epigenetics; fluorine; histone deacetylase; positron emission tomography