title: Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.
abstract: Histone deacetylases (HDAC's) became increasingly important targets for therapy of various diseases, resulting in a pressing need to develop HDAC class- and isoform-selective inhibitors. Class IIa deacetylases possess only minimal deacetylase activity against acetylated histones, but have several other client proteins as substrates through which they participate in epigenetic regulation. Herein, we report the radiosyntheses of the second generation of HDAC class IIa-specific radiotracers: 6-(di-fluoroacetamido)-1-hexanoicanilide (DFAHA) and 6-(tri-fluoroacetamido)-1-hexanoicanilide ([18F]-TFAHA). The selectivity of these radiotracer substrates to HDAC class IIa enzymes was assessed in vitro, in a panel of recombinant HDACs, and in vivo using PET/CT imaging in rats. [18F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [18F]DFAHA and previously reported [18F]FAHA. PET imaging with [18F]TFAHA can be used to visualize and quantify spatial distribution and magnitude of HDAC class IIa expression-activity in different organs and tissues in vivo. Furthermore, PET imaging with [18F]TFAHA may advance the understanding of HDACs class IIa mediated epigenetic regulation of normal and pathophysiological processes, and facilitate the development of novel HDAC class IIa-specific inhibitors for therapy of different diseases.
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Robin
authors.initials: R
authors.lastname: Bonomi
authors.affiliation: Center for Advanced Biomedical Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Shavrin
authors.affiliation: National Cyclotron and Radiochemistry Center, National Yang Ming University, Taipei, Taiwan; Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei, Taiwan.
authors.forename: Hsien-Hsien
authors.initials: HH
authors.lastname: Yeh
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Anjoy
authors.initials: A
authors.lastname: Majhi
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Sajeewa W
authors.initials: SW
authors.lastname: Dewage
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: Amer
authors.initials: A
authors.lastname: Najjar
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
authors.affiliation: Department of Chemistry, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: G Andrés
authors.initials: GA
authors.lastname: Cisneros
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: William P
authors.initials: WP
authors.lastname: Tong
authors.affiliation: Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States of America.
authors.forename: Mian M
authors.initials: MM
authors.lastname: Alauddin
authors.affiliation: National Cyclotron and Radiochemistry Center, National Yang Ming University, Taipei, Taiwan; Department of Biomedical Imaging and Radiological Sciences, National Yang Ming University, Taipei, Taiwan.
authors.forename: Ren-Shuan
authors.initials: RS
authors.lastname: Liu
authors.affiliation: Positron Emission Tomography Center, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Mangner
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Nashaat
authors.initials: N
authors.lastname: Turkman
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D003952:Diagnostic Imaging / Q000379:methods*; D044127:Epigenesis, Genetic; D005462:Fluorine Radioisotopes / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D011849:Radioactive Tracers; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D013379:Substrate Specificity; D014057:Tomography, X-Ray Computed / Q000379:methods
chemical_list: D005462:Fluorine Radioisotopes; D011849:Radioactive Tracers; D006655:Histone Deacetylases