title: Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain.
abstract: Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([(18)F]Fluoroacetamido)-1-hexanoicanilide ([(18)F]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [(18)F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.
authors.affiliation: Biosciences Department, Brookhaven National Laboratory, Upton, NY 11973, USA; Department of Chemistry, Chonbuk National University, Jeonju 561-756, South Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Seo
authors.forename: Lisa
authors.initials: L
authors.lastname: Muench
authors.forename: Alicia
authors.initials: A
authors.lastname: Reid
authors.forename: Jinzhu
authors.initials: J
authors.lastname: Chen
authors.forename: Yeona
authors.initials: Y
authors.lastname: Kang
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Hooker
authors.forename: Nora D
authors.initials: ND
authors.lastname: Volkow
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Fowler
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000813:Anilides / Q000737:chemistry; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging* / Q000201:enzymology*; D002250:Carbon Radioisotopes / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry; D005463:Fluoroacetates / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D049268:Positron-Emission Tomography; D011323:Primates; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000813:Anilides; D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D005463:Fluoroacetates; D056572:Histone Deacetylase Inhibitors; D019275:Radiopharmaceuticals; C007741:fluoroacetamide; D006655:Histone Deacetylases
keywords: Brain; Brain permeability; Carbon-11; Epigenetics; Positron emission tomography; SAHA