Open AccessNovel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain
Author(s) -
Robin E. Bonomi,
Utpal Mukhopadhyay,
Aleksandr Shavrin,
Hsien Hsien Yeh,
Anjoy Majhi,
Sajeewa W. Dewage,
Amer Najjar,
Xin Lu,
G. Andrés Cisneros,
William P. Tong,
Mian M. Alauddin,
Ren Shuan Liu,
Thomas J. Mangner,
Nashaat Turkman,
Juri G. Gelovani
Publication year - 2015
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0133512
Subject(s) - epigenetics , histone deacetylase , histone , in vivo , acetylation , chemistry , pet imaging , pharmacology , cancer research , biochemistry , positron emission tomography , biology , neuroscience , genetics , gene
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 ([ 18 F]-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. [ 18 F]TFAHA showed significantly higher selectivity for HDAC class IIa enzymes, as compared to [ 18 F]DFAHA and previously reported [ 18 F]FAHA. PET imaging with [ 18 F]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 [ 18 F]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.