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Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Bonomi R, Mukhopadhyay U, Shavrin A, Yeh HH, Majhi A, Dewage SW, Najjar A, Lu X, Cisneros GA, Tong WP, Alauddin MM, Liu RS, Mangner TJ, Turkman N, Gelovani JG - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.

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.

No MeSH data available.


The three parts of a HDAC substrate, the cap (red), the linker (green), and the leaving group (blue).
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pone.0133512.g006: The three parts of a HDAC substrate, the cap (red), the linker (green), and the leaving group (blue).

Mentions: It is important to note, that the entire structure of the substrate molecule plays a role in the selectivity for HDACs class IIa. The structure of HDAC substrates can be subdivided into three regions, which individually contribute to HDAC class and isoform selectivity: 1) the leaving group; 2) the linker; and 3) the capping moiety (Fig 6). Previous studies demonstrated that trifluoroacetyl group can be cleaved by HDAC 8 when it is attached to a lysine residue flanked by Boc and MCA (Boc-Lys(TFA)-MCA) [38]. In contrast, the phenyl capping group and lysine linker in DFAHA and TFAHA confer selectivity of these compounds only to HDAC Class IIa, with no significant affinity to HDAC8.


Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain.

Bonomi R, Mukhopadhyay U, Shavrin A, Yeh HH, Majhi A, Dewage SW, Najjar A, Lu X, Cisneros GA, Tong WP, Alauddin MM, Liu RS, Mangner TJ, Turkman N, Gelovani JG - PLoS ONE (2015)

The three parts of a HDAC substrate, the cap (red), the linker (green), and the leaving group (blue).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4526562&req=5

pone.0133512.g006: The three parts of a HDAC substrate, the cap (red), the linker (green), and the leaving group (blue).
Mentions: It is important to note, that the entire structure of the substrate molecule plays a role in the selectivity for HDACs class IIa. The structure of HDAC substrates can be subdivided into three regions, which individually contribute to HDAC class and isoform selectivity: 1) the leaving group; 2) the linker; and 3) the capping moiety (Fig 6). Previous studies demonstrated that trifluoroacetyl group can be cleaved by HDAC 8 when it is attached to a lysine residue flanked by Boc and MCA (Boc-Lys(TFA)-MCA) [38]. In contrast, the phenyl capping group and lysine linker in DFAHA and TFAHA confer selectivity of these compounds only to HDAC Class IIa, with no significant affinity to HDAC8.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48202, United States of America.

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.

No MeSH data available.