title: PET imaging demonstrates histone deacetylase target engagement and clarifies brain penetrance of known and novel small molecule inhibitors in rat.
abstract: Histone deacetylase (HDAC) enzymes have been demonstrated as critical components in maintaining chromatin homeostasis, CNS development, and normal brain function. Evidence in mouse models links HDAC expression to learning, memory, and mood-related behaviors; small molecule HDAC inhibitor tool compounds have been used to demonstrate the importance of specific HDAC subtypes in modulating CNS-disease-related behaviors in rodents. So far, no direct evidence exists to understand the quantitative changes in HDAC target engagement that are necessary to alter biochemistry and behavior in a living animal. Understanding the relationship between target engagement and in vivo effect is essential in refining new ways to alleviate disease. We describe here, using positron emission tomography (PET) imaging of rat brain, the in vivo target engagement of a subset of class I/IIb HDAC enzymes implicated in CNS-disease (HDAC subtypes 1, 2, 3, and 6). We found marked differences in the brain penetrance of tool compounds from the hydroxamate and benzamide HDAC inhibitor classes and resolved a novel, highly brain penetrant benzamide, CN147, chronic treatment with which resulted in an antidepressant-like effect in a rat behavioral test. Our work highlights a new translational path for understanding the molecular and behavioral consequences of HDAC target engagement.
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School , Charlestown, Massachusetts 02129, United States.
authors.forename: F A
authors.initials: FA
authors.lastname: Schroeder
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: G C
authors.initials: GC
authors.lastname: Van de Bittner
authors.forename: R
authors.initials: R
authors.lastname: Neelamegam
authors.forename: W R
authors.initials: WR
authors.lastname: Takakura
authors.forename: A
authors.initials: A
authors.lastname: Karunakaran
authors.forename: H Y
authors.initials: HY
authors.lastname: Wey
authors.forename: S A
authors.initials: SA
authors.lastname: Reis
authors.forename: J
authors.initials: J
authors.lastname: Gale
authors.forename: Y L
authors.initials: YL
authors.lastname: Zhang
authors.forename: E B
authors.initials: EB
authors.lastname: Holson
authors.forename: S J
authors.initials: SJ
authors.lastname: Haggarty
authors.forename: J M
authors.initials: JM
authors.lastname: Hooker
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001549:Benzamides / Q000493:pharmacokinetics / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003866:Depressive Disorder / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D056572:Histone Deacetylase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D051381:Rats
chemical_list: D000928:Antidepressive Agents; D001549:Benzamides; D002250:Carbon Radioisotopes; D056572:Histone Deacetylase Inhibitors; D019275:Radiopharmaceuticals; D006655:Histone Deacetylases
keywords: Neuroimaging epigenetics; preclinical; radiotracer; rodent; translational