title: Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹⁸F-FAHA.
abstract: Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDAC expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [(18)F]FAHA, a novel HDAC substrate, and [(18)F]fluoroacetate, the major radio-metabolite of [(18)F]FAHA, and fused with corresponding MR images of the brain. Quantification of [(18)F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [(18)F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [(18)F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.
authors.affiliation: Department of Experimental Diagnostic Imaging, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Hsin-Hsien
authors.initials: HH
authors.lastname: Yeh
authors.forename: Mei
authors.initials: M
authors.lastname: Tian
authors.forename: Rainer
authors.initials: R
authors.lastname: Hinz
authors.forename: Daniel
authors.initials: D
authors.lastname: Young
authors.forename: Alexander
authors.initials: A
authors.lastname: Shavrin
authors.forename: Uday
authors.initials: U
authors.lastname: Mukhapadhyay
authors.forename: Leo G
authors.initials: LG
authors.lastname: Flores
authors.forename: Julius
authors.initials: J
authors.lastname: Balatoni
authors.forename: Suren
authors.initials: S
authors.lastname: Soghomonyan
authors.forename: Hwan J
authors.initials: HJ
authors.lastname: Jeong
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pal
authors.forename: Rajesh
authors.initials: R
authors.lastname: Uthamanthil
authors.forename: James N
authors.initials: JN
authors.lastname: Jackson
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Nishii
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuma
authors.forename: Hirotaka
authors.initials: H
authors.lastname: Onoe
authors.forename: Shinya
authors.initials: S
authors.lastname: Kagawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Higashi
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Fukumitsu
authors.forename: Mian
authors.initials: M
authors.lastname: Alauddin
authors.forename: William
authors.initials: W
authors.lastname: Tong
authors.forename: Karl
authors.initials: K
authors.lastname: Herholz
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
mesh_terms: D000813:Anilides; D000818:Animals; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism*; D008253:Macaca mulatta; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D057054:Molecular Imaging / Q000379:methods*; D049268:Positron-Emission Tomography / Q000379:methods*; D013382:Subtraction Technique
chemical_list: C542233:6-(fluoroacetamido)-1-hexanoicanilide; D000813:Anilides; D005462:Fluorine Radioisotopes; D006655:Histone Deacetylases