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In Vivo Imaging of Histone Deacetylases (Hdacs) University of Groningen In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs Wang, Changning; Schroeder, Frederick A; Wey, Hsiao-Ying; Borra, Ronald; Wagner, Florence F; Reis, Surya; Kim, Sung Won; Holson, Edward B; Haggarty, Stephen J; Hooker, Jacob M Published in: Journal of Medicinal Chemistry DOI: 10.1021/jm500872p IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Wang, C., Schroeder, F. A., Wey, H-Y., Borra, R., Wagner, F. F., Reis, S., Kim, S. W., Holson, E. B., Haggarty, S. J., & Hooker, J. M. (2014). In vivo imaging of histone deacetylases (HDACs) in the central nervous system and major peripheral organs. Journal of Medicinal Chemistry, 57(19), 7999-8009. https://doi.org/10.1021/jm500872p Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 25-09-2021 This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. Article pubs.acs.org/jmc In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs † † ‡ † † § Changning Wang, Frederick A. Schroeder, , Hsiao-Ying Wey, Ronald Borra, Florence F. Wagner, ‡ ∥ § ‡ † Surya Reis, Sung Won Kim, Edward B. Holson, Stephen J. Haggarty, and Jacob M. Hooker*, † Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 73 High Street, Charlestown, Massachusetts 02129, United States ‡ Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States § Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States ∥ Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, United States *S Supporting Information ABSTRACT: Epigenetic enzymes are now targeted to treat the underlying gene expression dysregulation that contribute to disease pathogenesis. Histone deacetylases (HDACs) have shown broad potential in treatments against cancer and emerging data supports their targeting in the context of cardiovascular disease and central nervous system dysfunction. Development of a molecular agent for non-invasive imaging to elucidate the distribution and functional roles of HDACs in humans will accelerate medical research and drug discovery in this domain. Herein, we describe the synthesis and validation of an HDAC imaging agent, [11C]6. Our imaging results demonstrate that this probe has high specificity, good selectivity, and appropriate kinetics and distribution for imaging HDACs in the brain, heart, kidney, pancreas, and spleen. Our findings support the translational potential for [11C]6 for human epigenetic imaging. ■ INTRODUCTION far to investigate HDAC distribution17,18 are not compatible Eukaryotic cellular identity, growth, and homeostasis, extending with translational medicine. Therefore, our goal was to develop to the level of organs, systems, and whole organisms depends in a positron emission tomography (PET) imaging probe, which part on refined and adaptive regulatory control of gene can quantify the density of HDAC 1, 2, 3, and 6 in vivo. expression. Investigation of epigenetic mechanismsnon- Evaluating the expression and distribution of epigenetic genetic determinants of gene expression variabilityhas machinery in vivo will improve our understanding of their highlighted the role of chromatin modifying enzymes in relationship with disease and would provide an opportunity to integrating environmental cues into biological effects via intervene with treatment. changes in transcriptional activity. The challenge for HDAC research is developing a technique To date, much attention in this regard has been paid to the for quantifying the HDAC density that can be used in living − histone deacetylase (HDAC) family of enzymes.1 16 HDAC subjects. The non-invasive imaging technique, PET, is an enzymes are divided into four different classes based on excellent tool to visualize chromatin-modifying enzymes in sequence homology, cellular localization, and phylogenic animals and human. PET can provide molecular level insight relationships to yeast homologues: class I (HDACs 1, 2, 3, into protein density and interaction with drugs by quantifying and 8), class IIa (HDACs 4, 5, 7, and 9), class IIb (HDACs 6, the distribution of a radiotracer with extraordinarily high 10), class III (Sirtuins 1−7), and class IV (HDAC 11). sensitivity. To date there are no validated tools for assessing the Abnormal expression levels (both increased and decreased densities of HDAC enzymes in human despite the importance ff expression) of HDAC 1, 2, 3, and 6 that have been correlated of these enzymes and their remarkably high expression. E orts by others have resolved non-invasive probes for imaging with many diseases, including several forms of cancer, heart 19−23 failure, inflammatory diseases, and cognitive and psychiatric HDAC enzyme density in vivo, however these tools have disorders (Table 1). However, our knowledge of normal HDAC density and alterations in HDACs with human disease Received: June 9, 2014 remains extremely limited and invasive methodologies used so Published: September 9, 2014 © 2014 American Chemical Society 7999 dx.doi.org/10.1021/jm500872p | J. Med. Chem. 2014, 57, 7999−8009 Journal of Medicinal Chemistry Article Table 1. Selected Evidence of HDAC 1, 2, 3, and 6 Involvement in Diseases selected evidence of HDAC 1, 2, 3, and 6 disease/process involvement refs HDAC 1 and 3 protein complex integrity links 1, 2 deficient DNA repair with neurotoxicity HDAC 1 expression is elevated in vulnerable brain 3 neurodegenerative regions of mouse disease models disorders HDAC 2 is elevated in Alzheimer’s patient brain and 4 negatively impacts memory in animal models HDAC 6 overexpression in patients with AD 5 HDAC 1 overexpression in the prefrontal cortex 6 disrupts working memory learning and memory HDAC 2 loss improves working memory and 7 accelerates extinction learning HDAC 1 and 2 are critical mediators of autophagy 8 and cardiac plasticity heart failure Class I HDAC enzymes alter cardiomyocyte 9 hypertrophy via ERK kinase activity asthma HDAC 2 deficiency in cells blunts transcriptional 10 response to steroids and anti-inflammatory drugs. cancer (general) HDAC acetylation of p53 mediates tumor cell 11 survival breast cancer HDAC 6 mRNA expression may have potential 12 both as a marker of endocrine responsiveness and Figure 1. [11C]6: a translational PET imaging probe. We have as a prognostic indicator in breast cancer developed a potent HDAC imaging agent, termed [11C]6, HDAC 3 turnover is induced in cells by 13 isothiocyanate therapeutics incorporating three key structural features to create a versatile and colon cancer translational probe for visualizing HDAC expression in vivo. HDAC 1 and NuRD complex contributes to 14 11 epigenetic silencing of colorectal tumor Intravenous injection of trace amounts of [ C]6 (nanogram scale) suppressor genes in baboon and imaging by PET-MR demonstrates quantifiable uptake HDACs 1−3 overexpression confer cisplatin 15 in the brain and in diverse peripheral organs. This illustrates the resistance in ovarian cancer cell lines 11 ovarian cancer potential for [ C]6 as a broadly applicable tool in evaluating HDAC HDAC 1 and 3 overexpression mediate proliferation 16 density in humans. and migration of ovarian cancer cells ■ RESULTS Design and Synthesis of PET Imaging Agents with rapid binding kinetics and poor brain penetrating ability or bind Brain Permeability. HDAC inhibitors comprise diverse to a different subset of HDACs than the isoforms that have structural classes including hydroxamic acids, natural cyclic been extensively implicated in diseases via study of patients and peptides, and short-chain fatty acids as well as aminoanilines preclinical animal models. and ketones. Most classes of HDAC inhibitors contain three Herein, we report the development of [11C](E)-3-(4- main structural elements to their pharmacophore: (i) a capping ((((3r,5r,7r)-Adamantan-1-ylmethyl)(methyl)amino)methyl)- group, (ii) a linker domain, and (iii) a zinc-binding group, phenyl)-N-hydroxyacrylamide ([11C]Martinostat, [11C]6) (Fig- critical for enzyme action. Modification of these structural ure 1) as a molecule ready for translation to human PET elements has so far revealed that the brain uptake of most imaging
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