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

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• 作者：Hsin-Hsien Yeh^a ; ¹ ; Mei Tian^a ; ¹ ; Rainer Hinz^b ; ¹ ; Daniel Young^a ; Alexander Shavrin^a ; Uday Mukhapadhyay^a ; Leo G. Flores^a ; Julius Balatoni^a ; Suren Soghomonyan^a ; Hwan J. Jeong^a ; Ashutosh Pal^a ; Rajesh Uthamanthil^a ; James N. Jackson^a ; Ryuichi Nishii^c ; Hiroshi Mizuma^d ; Hirotaka Onoe^d ; Shinya Kagawa^e ; Tatsuya Higashi^e ; Nobuyoshi Fukumitsu^f ; Mian Alauddin^a ; William Tong^a ; Karl Herholz^b ; Juri G. Gelovani^a ; ^{jgelovani@mdanderson.org}
• 关键词：Epigenetics ; Histone deacetylases ; Positron emission tomography ; Brain ; Rhesus macaque
• 刊名：NeuroImage
• 出版年：2013
• 出版时间：1 January, 2013
• 年：2013
• 卷：64
• 期：Complete
• 页码：630-639
• 全文大小：1216 K

文摘

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.