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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.


PET/CT images (A) of the spatial and temporal dynamics of influx, distribution, clearance and retention of each of the three radiotracers at different time intervals after intravenous administration: [18F]FAHA (top panel), [18F]DFAHA (middle panel), and [18F]TFAHA (bottom panel). In each panel, PET/CT images are provided in three different planes: top row—axial images through the middle of the brain; middle row–coronal images through the middle of the brain; bottom row—coronal images through the cerebellum area. Images are color-coded to range of standard uptake values (SUV) shown in the color bar and cross-normalized to facilitate direct comparison of radioactivity distribution. Corresponding time-activity plots (B) of each radiotracer are provided on the right hand side for: cerebellum (blue diamonds), muscle (green triangles), cortex (red squares), and heart (grey crosshairs).
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pone.0133512.g011: PET/CT images (A) of the spatial and temporal dynamics of influx, distribution, clearance and retention of each of the three radiotracers at different time intervals after intravenous administration: [18F]FAHA (top panel), [18F]DFAHA (middle panel), and [18F]TFAHA (bottom panel). In each panel, PET/CT images are provided in three different planes: top row—axial images through the middle of the brain; middle row–coronal images through the middle of the brain; bottom row—coronal images through the cerebellum area. Images are color-coded to range of standard uptake values (SUV) shown in the color bar and cross-normalized to facilitate direct comparison of radioactivity distribution. Corresponding time-activity plots (B) of each radiotracer are provided on the right hand side for: cerebellum (blue diamonds), muscle (green triangles), cortex (red squares), and heart (grey crosshairs).

Mentions: The uptake, accumulation, and clearance of [18F]FAHA, [18F]DFAHA, and [18F]TFAHA in various regions of the rat brain were studied using dynamic PET/CT imaging. Higher levels of accumulation of all three radiotracers were observed primarily in n. accumbens, hippocampus, amygdala, periaqueductal grey, and cerebellum (Fig 11), where the HDACs 4 and 5 are abundantly expressed [16]. The alignment of the PET/CT images with the digital rat brain atlas [40] was used to identify regions of interest (Text A in S1 File; Fig A in S1 File). Highly selective accumulation of [18F]TFAHA-derived radioactivity was observed in the cerebellum, n. accumbens, periaqueductal gray, and hippocampus (dentate gyrus-CA1, CA3 region). The levels of [18F]TFAHA-derived radioactivity accumulation in these brain structures were higher than those from either [18F]DFAHA or [18F]FAHA. While [18F]FAHA exhibited moderate levels of radioactivity accumulation throughout the brain, including brain cortex, which is consistent with its higher substrate affinity to other HDAC classes, both [18F]DFAHA and, especially [18F]TFAHA, exhibited much lower accumulation in the cortex (Fig B in S1 File). Logan graphical analysis of [18F]FAHA, [18F]DFAHA and [18F]TFAHA accumulation in cerebellum using cortex as the reference tissue demonstrated that [18F]TFAHA was more actively accumulated (had a steeper slope of the Logan plot) in the cerebellar nuclei than either [18F]FAHA or [18F]DFAHA (Fig C in S1 File). Following PET/CT in vivo imaging with [18F]TFAHA, quantitative autoradiography (QAR) was performed in selected animals to verify the results at higher resolution of images. Fig D in S1 File demonstrates a high degree of correlation between the areas of 18F-TFAHA-derived accumulation displayed by autoradiography and the PET images shown in Fig A in S1 File. Higher levels of accumulation of [18F]TFAHA were observed using QAR in n. accumbens, hippocampus, periaqueductal grey, and in cerebellar nuclei.


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)

PET/CT images (A) of the spatial and temporal dynamics of influx, distribution, clearance and retention of each of the three radiotracers at different time intervals after intravenous administration: [18F]FAHA (top panel), [18F]DFAHA (middle panel), and [18F]TFAHA (bottom panel). In each panel, PET/CT images are provided in three different planes: top row—axial images through the middle of the brain; middle row–coronal images through the middle of the brain; bottom row—coronal images through the cerebellum area. Images are color-coded to range of standard uptake values (SUV) shown in the color bar and cross-normalized to facilitate direct comparison of radioactivity distribution. Corresponding time-activity plots (B) of each radiotracer are provided on the right hand side for: cerebellum (blue diamonds), muscle (green triangles), cortex (red squares), and heart (grey crosshairs).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526562&req=5

pone.0133512.g011: PET/CT images (A) of the spatial and temporal dynamics of influx, distribution, clearance and retention of each of the three radiotracers at different time intervals after intravenous administration: [18F]FAHA (top panel), [18F]DFAHA (middle panel), and [18F]TFAHA (bottom panel). In each panel, PET/CT images are provided in three different planes: top row—axial images through the middle of the brain; middle row–coronal images through the middle of the brain; bottom row—coronal images through the cerebellum area. Images are color-coded to range of standard uptake values (SUV) shown in the color bar and cross-normalized to facilitate direct comparison of radioactivity distribution. Corresponding time-activity plots (B) of each radiotracer are provided on the right hand side for: cerebellum (blue diamonds), muscle (green triangles), cortex (red squares), and heart (grey crosshairs).
Mentions: The uptake, accumulation, and clearance of [18F]FAHA, [18F]DFAHA, and [18F]TFAHA in various regions of the rat brain were studied using dynamic PET/CT imaging. Higher levels of accumulation of all three radiotracers were observed primarily in n. accumbens, hippocampus, amygdala, periaqueductal grey, and cerebellum (Fig 11), where the HDACs 4 and 5 are abundantly expressed [16]. The alignment of the PET/CT images with the digital rat brain atlas [40] was used to identify regions of interest (Text A in S1 File; Fig A in S1 File). Highly selective accumulation of [18F]TFAHA-derived radioactivity was observed in the cerebellum, n. accumbens, periaqueductal gray, and hippocampus (dentate gyrus-CA1, CA3 region). The levels of [18F]TFAHA-derived radioactivity accumulation in these brain structures were higher than those from either [18F]DFAHA or [18F]FAHA. While [18F]FAHA exhibited moderate levels of radioactivity accumulation throughout the brain, including brain cortex, which is consistent with its higher substrate affinity to other HDAC classes, both [18F]DFAHA and, especially [18F]TFAHA, exhibited much lower accumulation in the cortex (Fig B in S1 File). Logan graphical analysis of [18F]FAHA, [18F]DFAHA and [18F]TFAHA accumulation in cerebellum using cortex as the reference tissue demonstrated that [18F]TFAHA was more actively accumulated (had a steeper slope of the Logan plot) in the cerebellar nuclei than either [18F]FAHA or [18F]DFAHA (Fig C in S1 File). Following PET/CT in vivo imaging with [18F]TFAHA, quantitative autoradiography (QAR) was performed in selected animals to verify the results at higher resolution of images. Fig D in S1 File demonstrates a high degree of correlation between the areas of 18F-TFAHA-derived accumulation displayed by autoradiography and the PET images shown in Fig A in S1 File. Higher levels of accumulation of [18F]TFAHA were observed using QAR in n. accumbens, hippocampus, periaqueductal grey, and in cerebellar nuclei.

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.