Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with 18F-FAHA

Hsin Hsien Yeh; Mei Tian; Rainer Hinz; Daniel Young; Alexander Shavrin; Uday Mukhapadhyay; Leo G. Flores; Julius Balatoni; Suren Soghomonyan; Hwan J. Jeong; Ashutosh Pal; Rajesh Uthamanthil; James N. Jackson; Ryuichi Nishii; Hiroshi Mizuma; Hirotaka Onoe; Shinya Kagawa; Tatsuya Higashi; Nobuyoshi Fukumitsu; Mian Alauddin; William Tong; Karl Herholz; Juri G. Gelovani

doi:10.1016/j.neuroimage.2012.09.019

Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹⁸F-FAHA

Hsin Hsien Yeh, Mei Tian, Rainer Hinz, Daniel Young, Alexander Shavrin, Uday Mukhapadhyay, Leo G. Flores, Julius Balatoni, Suren Soghomonyan, Hwan J. Jeong, Ashutosh Pal, Rajesh Uthamanthil, James N. Jackson, Ryuichi Nishii, Hiroshi Mizuma, Hirotaka Onoe, Shinya Kagawa, Tatsuya Higashi, Nobuyoshi Fukumitsu, Mian AlauddinWilliam Tong, Karl Herholz, Juri G. Gelovani

Cancer Systems Imaging

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

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 [¹⁸F]FAHA, a novel HDAC substrate, and [¹⁸F]fluoroacetate, the major radio-metabolite of [¹⁸F]FAHA, and fused with corresponding MR images of the brain. Quantification of [¹⁸F]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 [¹⁸F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [¹⁸F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

Original language	English (US)
Pages (from-to)	630-639
Number of pages	10
Journal	NeuroImage
Volume	64
Issue number	1
DOIs	https://doi.org/10.1016/j.neuroimage.2012.09.019
State	Published - Jan 1 2013

Keywords

Brain
Epigenetics
Histone deacetylases
Positron emission tomography
Rhesus macaque

ASJC Scopus subject areas

Neurology
Cognitive Neuroscience

Access to Document

10.1016/j.neuroimage.2012.09.019

Cite this

Yeh, H. H., Tian, M., Hinz, R., Young, D., Shavrin, A., Mukhapadhyay, U., Flores, L. G., Balatoni, J., Soghomonyan, S., Jeong, H. J., Pal, A., Uthamanthil, R., Jackson, J. N., Nishii, R., Mizuma, H., Onoe, H., Kagawa, S., Higashi, T., Fukumitsu, N., ... Gelovani, J. G. (2013). Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹⁸F-FAHA. NeuroImage, 64(1), 630-639. https://doi.org/10.1016/j.neuroimage.2012.09.019

Yeh, HH, Tian, M, Hinz, R, Young, D, Shavrin, A, Mukhapadhyay, U, Flores, LG, Balatoni, J, Soghomonyan, S, Jeong, HJ, Pal, A, Uthamanthil, R, Jackson, JN, Nishii, R, Mizuma, H, Onoe, H, Kagawa, S, Higashi, T, Fukumitsu, N, Alauddin, M, Tong, W, Herholz, K & Gelovani, JG 2013, 'Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with ¹⁸F-FAHA', NeuroImage, vol. 64, no. 1, pp. 630-639. https://doi.org/10.1016/j.neuroimage.2012.09.019

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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 [18F]FAHA, a novel HDAC substrate, and [18F]fluoroacetate, the major radio-metabolite of [18F]FAHA, and fused with corresponding MR images of the brain. Quantification of [18F]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 [18F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [18F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.",

keywords = "Brain, Epigenetics, Histone deacetylases, Positron emission tomography, Rhesus macaque",

author = "Yeh, {Hsin Hsien} and Mei Tian and Rainer Hinz and Daniel Young and Alexander Shavrin and Uday Mukhapadhyay and Flores, {Leo G.} and Julius Balatoni and Suren Soghomonyan and Jeong, {Hwan J.} and Ashutosh Pal and Rajesh Uthamanthil and Jackson, {James N.} and Ryuichi Nishii and Hiroshi Mizuma and Hirotaka Onoe and Shinya Kagawa and Tatsuya Higashi and Nobuyoshi Fukumitsu and Mian Alauddin and William Tong and Karl Herholz and Gelovani, {Juri G.}",

note = "Funding Information: This work was supported by the grant 1RC2DA028912 ( NIDA, NIH ) to JG. ",

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doi = "10.1016/j.neuroimage.2012.09.019",

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T1 - Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with 18F-FAHA

AU - Yeh, Hsin Hsien

AU - Tian, Mei

AU - Hinz, Rainer

AU - Young, Daniel

AU - Shavrin, Alexander

AU - Mukhapadhyay, Uday

AU - Flores, Leo G.

AU - Balatoni, Julius

AU - Soghomonyan, Suren

AU - Jeong, Hwan J.

AU - Pal, Ashutosh

AU - Uthamanthil, Rajesh

AU - Jackson, James N.

AU - Nishii, Ryuichi

AU - Mizuma, Hiroshi

AU - Onoe, Hirotaka

AU - Kagawa, Shinya

AU - Higashi, Tatsuya

AU - Fukumitsu, Nobuyoshi

AU - Alauddin, Mian

AU - Tong, William

AU - Herholz, Karl

AU - Gelovani, Juri G.

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N2 - 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 [18F]FAHA, a novel HDAC substrate, and [18F]fluoroacetate, the major radio-metabolite of [18F]FAHA, and fused with corresponding MR images of the brain. Quantification of [18F]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 [18F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [18F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDAC inhibitor SAHA in the brain.

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