Novel Histone Deacetylase Class IIa Selective Substrate Radiotracers for PET Imaging of Epigenetic Regulation in the Brain
| Autor: | G. Andrés Cisneros, Thomas J. Mangner, Aleksandr Shavrin, Juri G. Gelovani, Nashaat Turkman, Hsien Hsien Yeh, William P. Tong, Anjoy Majhi, Mian M. Alauddin, Ren Shuan Liu, Xin Lu, Amer Najjar, Uday Mukhopadhyay, Sajeewa W. Dewage, Robin E. Bonomi |
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| Rok vydání: | 2015 |
| Předmět: |
Diagnostic Imaging
Fluorine Radioisotopes lcsh:Medicine Histone Deacetylases Epigenesis Genetic Substrate Specificity Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine In vivo Animals Epigenetics Radioactive Tracers lcsh:Science 030304 developmental biology chemistry.chemical_classification 0303 health sciences Multidisciplinary biology lcsh:R Brain Reproducibility of Results In vitro 3. Good health Histone Enzyme chemistry Biochemistry Acetylation Positron-Emission Tomography Cancer research biology.protein Autoradiography lcsh:Q Histone deacetylase Tomography X-Ray Computed 030217 neurology & neurosurgery Research Article Deacetylase activity |
| Zdroj: | PLoS ONE PLoS ONE, Vol 10, Iss 8, p e0133512 (2015) |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0133512 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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