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

H H Yeh; M Tian; R Hinz; D Young; A Shavrin; U Mukhapadhyay; L G Flores; J Balatoni; S Soghomonyan; H J Jeong; A Pal; R Uthamanthil; J N Jackson; R Nishii; H Mizuma; H Onoe; S Kagawa; T Higashi; N Fukumitsu; M Alauddin; W Tong; K Herholz; J G Gelovani

doi:10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

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

H H Yeh, M Tian, R Hinz, D Young, A Shavrin, U Mukhapadhyay, L G Flores, J Balatoni, S Soghomonyan, H J Jeong, A Pal, R Uthamanthil, J N Jackson, R Nishii, H Mizuma, H Onoe, S Kagawa, T Higashi, N Fukumitsu, M AlauddinW Tong, K Herholz, J G Gelovani

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

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.

Original language	English
Pages (from-to)	630-9
Number of pages	620
Journal	NeuroImage
Volume	64
DOIs	https://doi.org/10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]
Publication status	Published - 2013

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10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

http://www.ncbi.nlm.nih.gov/pubmed/22995777

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 (18)F-FAHA. NeuroImage, 64, 630-9. https://doi.org/10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

@article{7f6259e1069c40f49c77146aed62d937,

title = "Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with (18)F-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.",

author = "Yeh, {H H} and M Tian and R Hinz and D Young and A Shavrin and U Mukhapadhyay and Flores, {L G} and J Balatoni and S Soghomonyan and Jeong, {H J} and A Pal and R Uthamanthil and Jackson, {J N} and R Nishii and H Mizuma and H Onoe and S Kagawa and T Higashi and N Fukumitsu and M Alauddin and W Tong and K Herholz and Gelovani, {J G}",

note = "Yeh, Hsin-Hsien Tian, Mei Hinz, Rainer Young, Daniel Shavrin, Alexander Mukhapadhyay, Uday Flores, Leo G Balatoni, Julius Soghomonyan, Suren Jeong, Hwan J Pal, Ashutosh Uthamanthil, Rajesh Jackson, James N Nishii, Ryuichi Mizuma, Hiroshi Onoe, Hirotaka Kagawa, Shinya Higashi, Tatsuya Fukumitsu, Nobuyoshi Alauddin, Mian Tong, William Herholz, Karl Gelovani, Juri G RC2 DA028912/DA/NIDA NIH HHS/United States United States NeuroImage Neuroimage. 2013 Jan 1;64:630-9. doi: 10.1016/j.neuroimage.2012.09.019. Epub 2012 Sep 17.",

year = "2013",

doi = "10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]",

language = "English",

volume = "64",

pages = "630--9",

journal = "NeuroImage",

issn = "1095-9572",

publisher = "Elsevier BV",

}

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 (18)F-FAHA', NeuroImage, vol. 64, pp. 630-9. https://doi.org/10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

TY - JOUR

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

AU - Yeh, H H

AU - Tian, M

AU - Hinz, R

AU - Young, D

AU - Shavrin, A

AU - Mukhapadhyay, U

AU - Flores, L G

AU - Balatoni, J

AU - Soghomonyan, S

AU - Jeong, H J

AU - Pal, A

AU - Uthamanthil, R

AU - Jackson, J N

AU - Nishii, R

AU - Mizuma, H

AU - Onoe, H

AU - Kagawa, S

AU - Higashi, T

AU - Fukumitsu, N

AU - Alauddin, M

AU - Tong, W

AU - Herholz, K

AU - Gelovani, J G

N1 - Yeh, Hsin-Hsien Tian, Mei Hinz, Rainer Young, Daniel Shavrin, Alexander Mukhapadhyay, Uday Flores, Leo G Balatoni, Julius Soghomonyan, Suren Jeong, Hwan J Pal, Ashutosh Uthamanthil, Rajesh Jackson, James N Nishii, Ryuichi Mizuma, Hiroshi Onoe, Hirotaka Kagawa, Shinya Higashi, Tatsuya Fukumitsu, Nobuyoshi Alauddin, Mian Tong, William Herholz, Karl Gelovani, Juri G RC2 DA028912/DA/NIDA NIH HHS/United States United States NeuroImage Neuroimage. 2013 Jan 1;64:630-9. doi: 10.1016/j.neuroimage.2012.09.019. Epub 2012 Sep 17.

PY - 2013

Y1 - 2013

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 [(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.

AB - 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.

U2 - 10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

DO - 10.1016/j.neuroimage.2012.09.019 S1053-8119(12)00929-9 [pii]

M3 - Article

SN - 1095-9572

VL - 64

SP - 630

EP - 639

JO - NeuroImage

JF - NeuroImage

ER -

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

Abstract

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