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In Vivo Imaging of Histone Deacetylases (HDACs) in the Central Nervous System and Major Peripheral Organs

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† 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
*Telephone: 617-726-6596; E-mail: [email protected]
Cite this: J. Med. Chem. 2014, 57, 19, 7999–8009
Publication Date (Web):September 9, 2014
https://doi.org/10.1021/jm500872p

Copyright © 2014 American Chemical Society. This publication is licensed under CC-BY.

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Abstract

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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

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Eukaryotic cellular identity, growth, and homeostasis, extending to the level of organs, systems, and whole organisms depends in part on refined and adaptive regulatory control of gene expression. Investigation of epigenetic mechanisms—nongenetic determinants of gene expression variability—has highlighted the role of chromatin modifying enzymes in integrating environmental cues into biological effects via changes in transcriptional activity.
To date, much attention in this regard has been paid to the histone deacetylase (HDAC) family of enzymes. (1-16) HDAC enzymes are divided into four different classes based on sequence homology, cellular localization, and phylogenic relationships to yeast homologues: class I (HDACs 1, 2, 3, and 8), class IIa (HDACs 4, 5, 7, and 9), class IIb (HDACs 6, 10), class III (Sirtuins 1–7), and class IV (HDAC 11). Abnormal expression levels (both increased and decreased expression) of HDAC 1, 2, 3, and 6 that have been correlated with many diseases, including several forms of cancer, heart failure, inflammatory diseases, and cognitive and psychiatric disorders (Table 1). However, our knowledge of normal HDAC density and alterations in HDACs with human disease remains extremely limited and invasive methodologies used so far to investigate HDAC distribution (17, 18) are not compatible with translational medicine. Therefore, our goal was to develop a positron emission tomography (PET) imaging probe, which can quantify the density of HDAC 1, 2, 3, and 6 in vivo. Evaluating the expression and distribution of epigenetic machinery in vivo will improve our understanding of their relationship with disease and would provide an opportunity to intervene with treatment.
Table 1. Selected Evidence of HDAC 1, 2, 3, and 6 Involvement in Diseases
disease/processselected evidence of HDAC 1, 2, 3, and 6 involvementrefs
neurodegenerative disordersHDAC 1 and 3 protein complex integrity links deficient DNA repair with neurotoxicity 1, 2
HDAC 1 expression is elevated in vulnerable brain regions of mouse disease models 3
HDAC 2 is elevated in Alzheimer’s patient brain and negatively impacts memory in animal models 4
HDAC 6 overexpression in patients with AD 5
learning and memoryHDAC 1 overexpression in the prefrontal cortex disrupts working memory 6
HDAC 2 loss improves working memory and accelerates extinction learning 7
heart failureHDAC 1 and 2 are critical mediators of autophagy and cardiac plasticity 8
Class I HDAC enzymes alter cardiomyocyte hypertrophy via ERK kinase activity 9
asthmaHDAC 2 deficiency in cells blunts transcriptional response to steroids and anti-inflammatory drugs. 10
cancer (general)HDAC acetylation of p53 mediates tumor cell survival 11
breast cancerHDAC 6 mRNA expression may have potential both as a marker of endocrine responsiveness and as a prognostic indicator in breast cancer 12
colon cancerHDAC 3 turnover is induced in cells by isothiocyanate therapeutics 13
HDAC 1 and NuRD complex contributes to epigenetic silencing of colorectal tumor suppressor genes 14
ovarian cancerHDACs 1–3 overexpression confer cisplatin resistance in ovarian cancer cell lines 15
HDAC 1 and 3 overexpression mediate proliferation and migration of ovarian cancer cells 16
The challenge for HDAC research is developing a technique for quantifying the HDAC density that can be used in living subjects. The non-invasive imaging technique, PET, is an excellent tool to visualize chromatin-modifying enzymes in animals and human. PET can provide molecular level insight into protein density and interaction with drugs by quantifying the distribution of a radiotracer with extraordinarily high sensitivity. To date there are no validated tools for assessing the densities of HDAC enzymes in human despite the importance of these enzymes and their remarkably high expression. Efforts by others have resolved non-invasive probes for imaging HDAC enzyme density in vivo, (19-23) however these tools have rapid binding kinetics and poor brain penetrating ability or bind to a different subset of HDACs than the isoforms that have been extensively implicated in diseases via study of patients and preclinical animal models.
Herein, we report the development of [11C](E)-3-(4-((((3r,5r,7r)-Adamantan-1-ylmethyl)(methyl)amino)methyl)phenyl)-N-hydroxyacrylamide ([11C]Martinostat, [11C]6) (Figure 1) as a molecule ready for translation to human PET imaging (HDAC 1, 2, 3, and 6). Compound 6 is an adamantane-based hydroxamic acid with selective binding to HDAC 1, 2, 3, and 6 with subnanomolar potency and fast binding kinetics. Using rodent and nonhuman primate PET imaging, we demonstrate robust uptake and high specific binding in brain, heart, spleen, kidney, and pancreas. Using this tool, measurement of HDAC density of target isoforms 1, 2, 3, and 6 is possible in peripheral organs and brain for the first time. Measuring HDAC target density/occupancy with the aformentioned non-invasive tool promises a major advance to understand epigenetic mechanism in normal body tissues and diseases. Self-blocking experiments have demonstrated the sensitivity of [11C]6 to resolve differences in HDAC expression in peripheral organs and brain. Further, blocking experiments with the clinical approved HDAC inhibitor, SAHA, underscore the utility of this tool to evaluate HDAC density and target engagement with different therapeutics. Taken together, our findings highlight the immediate utility of [11C]6 as a preclinical PET tool to investigate HDAC expression in animal models. Furthermore, we outline and discuss the optimal properties of [11C]6 as an HDAC radiotracer that strongly support its development as a clinical research tool.

Figure 1

Figure 1. [11C]6: a translational PET imaging probe. We have developed a potent HDAC imaging agent, termed [11C]6, incorporating three key structural features to create a versatile and translational probe for visualizing HDAC expression in vivo. Intravenous injection of trace amounts of [11C]6 (nanogram scale) in baboon and imaging by PET-MR demonstrates quantifiable uptake in the brain and in diverse peripheral organs. This illustrates the potential for [11C]6 as a broadly applicable tool in evaluating HDAC density in humans.

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Results

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Design and Synthesis of PET Imaging Agents with Brain Permeability

HDAC inhibitors comprise diverse structural classes including hydroxamic acids, natural cyclic peptides, and short-chain fatty acids as well as aminoanilines and ketones. Most classes of HDAC inhibitors contain three main structural elements to their pharmacophore: (i) a capping group, (ii) a linker domain, and (iii) a zinc-binding group, critical for enzyme action. Modification of these structural elements has so far revealed that the brain uptake of most HDAC inhibitors is limited. (19, 24) To develop an HDAC PET probe with broad disease applicability, we wanted to integrate a chemical structure that would exhibit robust exposure to both peripheral organs and the brain. In medicinal chemistry efforts by others, the adamantyl group has been identified as a structural subunit that confers CNS distribution in several drugs classes including antiviral drugs, (25) cannabinoid receptor modulators. (26) Further, adamantane-based hydroxamic acids were recently reported and showed strong evidence of HDAC inhibition. (27) Using these previous studies to guide our synthesis efforts, we designed compound 6, a cinnamic acid-based HDAC inhibitor containing an adamantyl group as a ‘blood brain barrier (BBB) carrier’ (Figure 1). Compound 6 was synthesized through reductive amination, followed by conversion into a hydroxamic acid in the presence of hydroxylamine and sodium hydroxide. The radiosynthesis of [11C]6 was accomplished using its desmethyl precursor in DMSO with [11C]methyl iodide ([11C]CH3I) as outlined in Scheme 1.

Scheme 1

Scheme 1. Synthesis of 6, Its Radiolabeling Precursor (4) and [11C]6a
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Scheme aReagents and conditions: (a) NaBH4, MeOH, overnight, rt, 75%; (b) formaldehyde, AcOH, NaBH4, MeOH, rt, overnight, 55%. (c) NH2OH (aq), 1M NaOH, MeOH/THF, 0 °C to rt, 4 h, 42% for 6, 40% for 5; RCY of [11C]6, 3–5% (non-decay corrected to trapped [11C]CH3I).

Physicochemical Properties of 6 and ex Vivo Binding

The in vitro inhibitory activities of 6 were measured for each HDAC isoform HDAC1 through HDAC9 (Table 2) using recombinant human enzymes, with IC50 values for the FDA approved HDAC inhibitor drug, suberoylanilide hydroxamic acid, vorinostat (SAHA), measured in parallel as a reference (to assess the variability among different assays). Compound 6 showed nanomolar IC50 values for class-I HDAC isoforms (HDAC 1–3, 0.3, 2.0, and 0.6 nM, respectively), and the class-IIb HDAC 6 (4.1 nM), with >100-fold selectivity over each of the other HDAC isoforms assayed. Using [11C]6 in vitro, we measured the partition coefficient (log D) at 2.03 and calculated tPSA of 52.5, which are in the preferred range for brain penetration, and further detected plasma protein binding (PPB), as measured in blood from baboon (1.4% unbound) and human (5.5% unbound), at levels consistent with those for the clinical dopamine D2 receptor radiotracer, [11C]raclopride (28) (Figure S1).
Table 2. HDAC Selectivity, Potency, and Efficacy of 6 Compared To SAHAa
assay6SAHA
IC50 (nM)
HDAC 10.34.0
HDAC 22.011
HDAC 30.63.0
HDAC 41970>30000
HDAC 53528750
HDAC 64.12.0
HDAC 7>20000>30000
HDAC 8>150001020
HDAC 9>15000>30000
EC50 (nM)
H3K9ac1003400
H4K12ac1001900
a

In vitro IC50 (nM) values using recombinant human enzymes for HDAC subtypes 1–9 and specific substrates demonstrate that 6 is a selective inhibitor of HDAC 1–3 (0.3–2.0 nM) with decreased potency to inhibit HDAC 6 (4.1 nM) or other subtypes (>352 nM). Comparatively, the hydroxamate HDAC inhibitor SAHA exhibited lower affinity for HDAC targets 1–3 (3.0–11 nM). Dose–response plots in cultured primary mouse neuronal cells measuring relative H3K9ac and H4K12ac levels revealed potent induction of histone acetylation (EC50) by 6 (100 nM) compared to SAHA (1900–3400 nM).

To test the selective binding of 6 over other potential protein targets, we screened the percentage inhibition of 6 (50 nM) using radioligand displacement assay against 4 zinc-dependent enzymes including matrix metalloproteinases and 80 additional non-HDAC or Zn-dependent central nervous system (CNS) targets. We determined minimal if any off-target binding, indicating high selectivity of 6 to the HDAC family (Table S1). The only potential off-target binding was the dopamine transporter (DAT) as implicated by the in vitro test. 6 (50 nM) resulted in a 24% inhibition of DAT (where 50% inhibition is the minimum threshold to identify a potential binding event). Therefore, to exclude a putative binding interaction of 6 to DAT (given that it is a relatively high dentistry brain protein), we used the established radiotracer [11C]β-CFT to evaluate DAT density/occupancy in rats and observed no impact of 6 treatment (1 mg/kg, ip, 90 min prior) (Figure S2).
To further establish that [11C]6 binding was specific for HDAC targets, we conducted blocking studies via autoradiography on rat brain sections ex vivo. We observed that specific binding of [11C]6 was reduced by preincubation of sagittal rat brain sections with either of the unlabeled HDAC inhibitors: SAHA, a hydroxamic acid-based HDAC inhibitor (selective for class I and IIb HDAC isoforms), or CI-994, a benzamide-based HDAC inhibitor (selective for HDAC 1, 2, and 3 isoforms) (Figure S1C,D).

In Vivo PET-CT Imaging with [11C]6 in Rodents

High Brain Uptake and Reversible Binding

To first test [11C]6 as a radiotracer in vivo, we conducted PET imaging focused on rat brain. Using PET-CT, we determined that [11C]6 exhibited high BBB penetration and sustained binding over the scanning time (60 min) when administered by intravenous bolus injection (0.9–1.1 mCi per animal), as shown in Figure S3A. To confirm that [11C]6 was not effluxed from the brain by the xenobiotic pump, P-glycoprotein (P-gp), we measured radioligand uptake in brain after treatment with the P-gp inhibitor, cyclosporin A (CsA), and found no difference compared to control treatment (Figure S4A). Additionally, [11C]6 binding in the rat brain was disrupted by an iv challenge with unlabeled 6 20 min after tracer administration as evidenced by a rapid decrease in the time–activity curve slope. This rapid loss of radioactivity from brain regions provided confirmation of the reversibility of [11C]6 binding to CNS targets (Figure S4B).
To determine the stability of [11C]6 in brain, we measured the presence of radiolabeled parent compound and polar metabolites in homogenized rat brain tissue 30 min post-in vivo injection of [11C]6. By eluting extracted and homogenized rat brain with solvents containing fractional increases of acetonitrile in water, we resolved a pattern of radioactivity indicating intact parent compound in the brain with limited degradation over the duration of a typical 30–90 min PET scan (Figure S5A). A similar pattern indicating unmetabolized [11C]6 was observed in baboon plasma, 5 min post-injection of the tracer (Figure S5B).

Dose-Dependent Blockade

To investigate the specificity of [11C]6, we performed PET imaging studies in rats with a 5 min pretreatment of unlabeled 6 at different doses (0.001, 0.1, 0.5, and 2.0 mg/kg). We found that [11C]6 binding in brain was blocked in a dose-dependent manner with a stepwise reduction in the percent tracer uptake after administration of unlabeled 6 (Figure S3B). To test the sensitivity of [11C]6 against other HDAC inhibitors, we pretreated a rat with CN54, a highly brain penetrant hydroxamic acid HDAC inhibitor as determined by LC-MS-MS (brain/plasma = 4.5 after 20 min administration of CN54 at 10 μg/kg via iv), and SAHA, a hydroxamic acid HDAC inhibitor with limited brain penetrating ability. (24) As expected, there was robust in vivo blockade of radioactivity in brain with the treatment of CN54, but not SAHA (Figure S3C).

In Vivo PET-MR Imaging with [11C]6 in Baboon

High Uptake in the Brain and Dose-Dependent Blockade

Next, we chose to utilize nonhuman primates to evaluate the distribution and specificity of [11C]6. In baboons, we found that high brain uptake (50–60 in VT, total volume of distribution) of [11C]6 based on PET-MR focused on the head. Similar to the blocking results we obtained in rats, injection of unlabeled 6 (0.5 and 1.0 mg/kg, iv) dose-dependently reduced the radioactivity uptake (measured as VT) in specific brain regions including cerebellum, cortex, putamen, and caudate (Figure 2). The averaged Bmax of whole brain, 19.6 ± 2.9 μM of protein, was calculated from the PET image on the basis of the established relationship between total binding and dissociation rate (29) and was consistent with ex vivo protein quantification in rodents by two methods. (30) Physiological effects (i.e., respiration rate, blood pressure, heart rate, and end-tidal CO2) were unchanged at any administered dose of 6 or [11C]6. The baboons used in these imaging studies were not sacrificed.

Figure 2

Figure 2. Kinetic modeling results with [11C]6 in baboon brain. (A) The total volume of distribution (VT) images from one representative animal show robust differences in radiotracer uptake at baseline and after blocking (0.5 mg/kg iv, 10 min pretreatment); (B) Two independent baseline-blocking studies were used to resolve quantitative VT data which show that pretreatment with unlabeled 6 (0.5 or 1.0 mg/kg) dose-dependently blocks tracer uptake in different baboon brain regions. WB: whole brain; CB: cerebellum; M1: primary motor cortex ; PU: putamen; TH: thalamus; V1: primary visual cortex ; CA: caudate; WM: white matter.

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Arterial Plasma Analysis

After [11C]6 intravenous bolus injection, radioactivity in arterial plasma clears rapidly as expected and as depicted in Figure S5C. Polar metabolites were observed in the plasma (50% of the plasma radioactivity after 10 min); however, radioactivity in brain tissue of rodents at late time points (30 min post administration) was associated almost exclusively with the parent molecule. These data support that the PET images for the brain tissue largely represent [11C]6 and not radiolabeled metabolites. For quantitative analysis of the NHP PET imaging data, a metabolite-corrected arterial input function was used.

Kinetic Modeling Shows High Specific Binding

Two-tissue compartmental modeling was applied to analyze dynamic [11C]6 PET data, corrected for arterial input function and parent compound metabolism to interpret results from intact and perfused radiotracer. Based on the modeling results (Figure 2), blocking with 0.5 and 1.0 mg/kg, VT decreased in all brain regions. Based on our rodent experiments and dose-equilibration for body mass, we assumed that a 1.0 mg/kg dose would provide full saturation of HDAC binding. Therefore, 50–80% of the signal represented specific binding in the selected brain regions suggesting that [11C]6 has sufficient sensitivity to assess a wide range of CNS diseases in which HDAC may be altered, such as Alzheimer’s disease and in mood disorders, (4, 31, 32) and for evaluation of drug-HDAC engagement.

High uptake and blockade in peripheral organs

We further evaluated the tracer uptake and blockade in peripheral organs in baboons. [11C]6 showed high uptake in major organs including heart, kidney, pancreas, and spleen (Figure 3). The uptake in these organs was markedly decreased by pretreatment with unlabeled 6, indicating that the [11C]6 signal also represents HDAC expression in peripheral organs. To further confirm the sensitivity of [11C]6 to detect changes in HDAC occupancy, we measured radiotracer uptake in the baboon both before and after 75 min infusion of SAHA (5 mg/kg, iv). We found that radiotracer uptake in peripheral tissue was robustly blocked by SAHA infusion, consistent with efficient distribution of this HDAC inhibitor blocking agent in nonbrain organs (24) (Figure S6).

Figure 3

Figure 3. [11C]6 PET-MR imaging. Axial views of summed PET images (40–80 min) superimposed with MR images from the same baboon following injection of radiotracer (4 mCi/baboon). Images illustrate tracer uptake in organs of interest at baseline and after pretreatment with unlabeled 6 (0.5 mg/kg). Robust blocking was observed in organs of interest including: A, heart; B, spleen; C, kidneys; and D, pancreas. Time–activity curves (baseline, blue; blocking, red) demonstrate a high specific binding of [11C]6 in these peripheral organs as the percent injected tracer dose per cm3 tissue is markedly reduced by blocking.

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Discussion

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Epigenetic therapies that target regulatory mechanisms of the human genome represent an emerging class of novel therapeutic agents. The importance of understanding aberrant enzyme expression of chromatin modifying enzymes including HDACs is highlighted by the discovery that protein coding mutations may play a role in human disease pathologies linked to cancer in major organs, cardiac dysfunction, and CNS disorders. The impact of these enzyme density changes is further implicated in disease as recent large-scale genome-wide association studies (GWAS) have shown that gene regulatory regions key in many common human diseases harbor an enrichment of single nucleotide polymorphisms (SNPs). (33-38) This evidence of deregulated gene expression mechanism points to a more general need to target epigenetic machinery that may be causally involved in disease pathogenesis. Therefore, developing therapeutics for many human diseases can be best accomplished by first understanding the density and distribution of epigenetic machinery including HDAC enzymes in vivo.
Development of specific PET radiotracers to measure HDAC density or any other epigenetic component, with high uptake and major organs, is challenging. (39) There are a number of major factors (summarized here A through D) that determine the success of a radiotracer candidate. Some factors can be predicted from in vitro assays (e.g., binding affinity and selectivity), and those which are more empirically determined (e.g., specific to nonspecific binding ratio). (A) The binding affinity and selectivity of a radiotracer for its target must be high enough to produce sufficient signal to background for detection and selective for the target so that images represent the biological target. (B) Additionally, radiotracers must exhibit specific binding, which is challenging to predict but can be easily measured by presaturating the target with an unlabeled (nonradioactive) form of the radiotracer thus resulting in decreased binding of radiotracer to its target. Unlabeled compound binding is also expected to alter the distribution and pharmacokinetics of the radioligand. (C) For CNS imaging, small molecules must cross the BBB. In general, small molecular weight (<400 Da) molecules with relatively high lipophilicity are required for a tracer to sufficiently penetrate the BBB. Predictive models based on PET imaging data are emerging for HDAC inhibitors that suggest the total polar surface area (tPSA) needs to be <65. (22) (D) With all of the above properties satisfied, a tracer candidate can still be rendered unusable in vivo if it is metabolized rapidly and those metabolites pervade the tissue regions of interest. Each of the primary factors for a successful radiotracer is met by [11C]6 and supported by our biochemical and preclinical imaging data. Of the more than 100 compounds we assessed through our tracer identification work, [11C]6 was unique. While we have observed some trends in molecular properties, structure, and in vivo behavior, fully understanding the molecular basis for [11C]6 success will require additional structure–activity relationship determination and computational modeling.
Our data support [11C]6 as a new tool to visualize HDAC density in the body and brain. The robust and blockable brain uptake with [11C]6 as a PET probe can be used to quantify HDAC density in brain disorders, such as neurodegenerative diseases and mood disorders, and for demonstrating target engagement of putative HDAC inhibitor therapeutics early in compound development pipeline. We found stable probe uptake in diverse peripheral organs in nonhuman primates, each with a distinct profile of HDAC target density and affinity as evidenced by time–activity curve (TAC) shape (Figure S6). In each case, we further demonstrated that [11C]6 binding could be prevented using a known, clinically applied HDAC inhibitor drug (Figure S6) illustrating the direct utility of this probe for understanding systemic impact of a cancer therapeutic. A recent report demonstrates that class I HDAC inhibition by a prototypical HDACi therapeutic, MS-275, stimulates renal dysfunction. (40) Dose-limiting toxicity may not be surprising given the widespread expression and central role of HDACs in normal biological function. However, this underscores a mechanism-based liability for HDAC inhibitor leads proposed to date as CNS disease therapeutics where large mass dosing strategies are used to reach effective concentrations of HDACi in brain. (24, 41, 42) Importantly, the ability to simultaneously measure HDAC target engagement in peripheral organs and brain is a major development in not only understanding CNS disease mechanisms but also in prioritizing novel HDAC inhibitors with minimal systemic burden.
In summary, [11C]6 binds to HDAC subtypes (HDAC 1, 2, 3, and 6) with high selectivity and specificity and provides a tool for quantitative imaging of HDAC density in the brain and in peripheral organs in vivo. [11C]6 can be used as a PET radioligand for studying HDACs in disorders where altered regulation of HDACs is found. The approach is also valuable for evaluation of potential drugs in vivo, therapy response can be compared in the same animal before drug treatment. Safety and toxicology studies have been completed, and we are progressing [11C]6 forward for evaluation as the first HDAC PET radiotracer and a novel class of epigenetic imaging probes in humans.

Experimental Section

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General Methods and Materials

All reagents and solvents were of ACS-grade purity or higher and used without further purification. NMR data were recorded on a Varian 500 MHz magnet and were reported in ppm units downfield from trimethylsilane. Analytical separation was conducted on an Agilent 1100 series HPLC fitted with a diode-array detector, quaternary pump, vacuum degasser, and autosampler. Mass spectrometry data were recorded on an Agilent 6310 ion trap mass spectrometer (ESI source) connected to an Agilent 1200 series HPLC with quaternary pump, vacuum degasser, diode-array detector, and autosampler. The precursor and compound 6 were synthesized (from Sai Life Sciences Ltd.) with >98% purity, as determined by a high-pressure liquid chromatography (HPLC) system (YMC TRIART C-18 (150 mm × 4.6 mm × 3 u) mobile phase: A: 0.05% TFA in water/B: 0.05% TFA in acetonitrile. Flow rate: 1.0 mL/min. Gradient: 15% B to 95% B in 8.0 min, hold until 9.5 min, 15% B in 13.0 min hold until 15.0 min. The quantitative NMR test were conducted by Sai Life Sciences Ltd., and 1,4-dimethoxybenzene was used as the reference. [11C]CO2 (1.2 Ci) was obtained via the 14N (p, α)11C reaction on nitrogen with 2.5% oxygen, with 11 MeV protons (Siemens Eclipse cyclotron), and trapped on molecular sieves in a TRACERlab FX-MeI synthesizer (General Electric). [11C]CH4 was obtained by the reduction of [11C]CO2 in the presence of Ni/hydrogen at 350 °C and recirculated through an oven containing I2 to produce 11CH3I via a radical reaction.
All animal studies were carried out at Massachusetts General Hospital (PHS Assurance of Compliance no. A3596-01). The Subcommittee on Research Animal Care (SRAC) serves as the Institutional Animal Care and Use Committee (IACUC) for the Massachusetts General Hospital (MGH). SRAC reviewed and approved all procedures detailed in this paper.
PET-MR imaging was performed in anesthetized (ketamine, isoflurane) baboon (Papio anubis) to minimize discomfort. Highly trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for daily care. All animals were socially housed in cages appropriate for the physical and behavioral health of the individual animal. Animals were fed thrice per diem, with additional nutritional supplements provided as prescribed by the attending veterinarian. Audio, video, and tactile enrichment was provided on a daily basis to promote psychological well-being. No nonhuman primates were euthanized to accomplish the research presented.
PET-CT imaging was performed in anesthetized (isoflurane) rats (Sprague–Dawley) to minimize discomfort. Highly trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for daily care. All animals were socially housed in cages appropriate for the physical and behavioral health of the individual animal. Animals were given unlimited access to food and water, with additional nutritional supplements provided as prescribed by the attending veterinary staff. Animals were euthanized at the end of the study using sodium pentobarbital (200 mg/kg, ip).

Chemical Synthesis

(E)-Methyl 3-(4-((((3r,5r,7r)-adamantan-1-ylmethyl)amino)methyl)phenyl)acrylate (3)

Adamantan-1-ylmethanamine (1) (1g, 6.0 mmol) and (E)-methyl 3-(4-formylphenyl)acrylate (2) (1 g, 5.3 mmol) was dissolved in MeOH (30 mL), and the mixture was stirred at room temperature for 2 h. Sodium borohydride (0.61g, 16 mmol) was then added, and the suspension was stirred overnight at room temperature. The white precipitate was filtered and dried to obtain the product 3 (1.35 g, yield: 75%).1H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 16 Hz, 1H), 7.48 (d, J = 7 Hz, 2H), 7.35 (d, J = 7 Hz, 2H), 6.43 (d, J = 16 Hz, 1H), 3.81 (s, 2H), 3.80 (s, 3H), 2.23 (s, 3H), 1.96 (s, 3H), 1.63–1.73 (m, 6H), 1.53 (s, 6H); 13C NMR (125 MHz, CDCl3): 167.55, 144.78, 143.81, 132.87, 128.35 (2C), 128.08 (2C), 117.10, 62.15, 54.28, 51.65, 40.85 (3C), 37.24 (3C), 33.49, 28.48 (3C). LC-MS calculated for C22H29NO2 expected [M]: 339.2; Found [M + H]+: 340.3.

(E)-3-(4-((((3r,5r,7r)-Adamantan-1-ylmethyl)amino)methyl)phenyl)-N-hydroxyacrylamide (4)

To a solution of 3 (0.5 g, 1.5 mmol) in MeOH/THF (5 mL/5 mL) at 0 °C was added NH2OH (50% aq solution, 3 mL) followed by 1 M NaOH (2 mL). The mixture was stirred at 0 °C for 2 h, warmed to room temperature, and stirred for 2 h. Acidification with 1 M HCl to pH 7–8 (pH paper) resulted in product precipitation. The precipitate was filtered and dried to obtain 4 (0.2 g, 40%) as white solid. 1H NMR (500 MHz, CDCl3): δ 7.69 (d, J = 16 Hz, 1H), 7.47 (d, J = 7.5 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H), 6.42 (d, J = 16 Hz, 1H), 3.80 (s, 3H), 3.54 (s, 2H), 2.19 (s, 3H), 2.10 (s, 2H), 1.95 (s, 3H), 1.62–1.723 (m, 6H), 1.53 (s, 6H); 13C NMR (125 MHz, CDCl3): 164.92, 141.31, 139.69, 133.75, 128.61 (2C), 127.42 (2C), 116.88, 71.09, 61.08, 53.31, 40.41 (3C), 36.77 (3C), 32.84, 28.48 (3C). LC-MS calculated for C21H28N2O2 expected [M]: 340.5; Found [M + H]+: 341.3. HPLC purity: 98.09%. Quantitative NMR purity: 95.10%.

(E)-Methyl 3-(4-((((3r,5r,7r)-adamantan-1-ylmethyl) (methyl) amino) methyl) phenyl) acrylate (5)

To a solution of 3 (0.5 g, 1.5 mmol) in MeOH (30 mL) was added formaldehyde (33% aq solution, 2 mL) followed by acetic acid (0.1 mL). The mixture was stirred at room temperature for 2 h. Sodium borohydride (0.61g, 16 mmol) was then added, and the suspension was stirred overnight at room temperature. The white precipitate was filtered and purified by flash chromatography in hexanes:ethyl acetate (4:1) to obtain the product 3 (0.29 g, yield: 55%) as white solid. 1H NMR (500 MHz, MeOH-d4): δ 7.55 (d, J = 16 Hz, 1H), 7.52 (d, J = 7.5 Hz, 2H), 7.37 (d, J = 7.5 Hz, 2H), 6.47 (d, J = 16 Hz, 1H), 3.77 (s, 2H), 2.21 (s, 2H), 1.94 (s, 3H), 1.66–1.76 (m, 6H), 1.54–1.55 (m, 6H); 13C NMR (125 MHz, MeOH-d4): 164.93, 141.32, 139.71, 133.76, 128.62 (2C), 127.43 (2C), 116.8901, 61.08, 53.32, 40.42 (3C), 36.78 (3C), 32.84, 28.48 (3C). LC-MS calculated for C21H28N2O2 expected [M]: 353.2; Found [M + H]+: 354.1.

(E)-3-(4-((((3r,5r,7r)-Adamantan-1-ylmethyl)(methyl)amino)methyl)phenyl)-N-hydroxyacrylamide (6)

To a solution of 5 (0.5 g, 1.4 mmol) in MeOH/THF (3 mL/3 mL) at 0 °C was added NH2OH (50% aq solution, 3 mL) followed by 1 M NaOH (2 mL). The mixture was stirred at 0 °C for 2 h, warmed to room temperature, and stirred for 2 h. Acidification with 1 M HCl to pH 7–8 (pH paper) resulted in product precipitation. The precipitate was filtered and dried to obtain 6 (0.21 g, 42%) as white solid. 1H NMR (500 MHz, DMSO-d6): δ 7.49 (d, J = 7.5 Hz, 2H), 7.42 (d, J = 16 Hz, 1H), 7.33 (d, J = 7.5 Hz, 2H), 6.45 (d, J = 16 Hz, 1H), 3.48 (s, 2H), 2.11 (s, 3H), 2.06 (s, 2H), 1.89 (s, 3H), 1.55–1.65 (m, 6H), 1.46 (s, 6H); δ 13C NMR (125 MHz, DMSO-d6): 163.15, 142.00, 138.43, 139.91, 129.36 (2C), 127.77 (2C), 119.06, 70.12, 64.57, 45.71, 41.01 (3C), 37.21 (3C), 35.27, 28.33 (3C). LC-MS calculated for C22H30N2O2 expected [M]: 354.2; Found [M + H]+: 355.3. HPLC purity: 99.64%. Quantitative NMR purity: 97.05%.

HDAC Inhibition Assay

All recombinant human HDACs were purchased from BPS Bioscience. The substrates, Broad Substrates A and B, were synthesized in house. All other reagents were purchased from Sigma-Aldrich. Caliper EZ reader II system was used to collect all data. HDAC inhibition assays: Compounds were tested in a 12-point dose curve with 3-fold serial dilution starting from 33.33 μM. Purified HDACs were incubated with 2 μM (the concentration is kept the same for all the HDACs, below Km of substrate) carboxyfluorescein (FAM)-labeled acetylated or trifluoroacetylated peptide substrate (Broad Substrates A and B, respectively) and test compound for 60 min at room temperature, in HDAC assay buffer that contained 50 mM HEPES (pH 7.4), 100 mM KCl, 0.01% BSA, and 0.001% Tween-20. Reactions were terminated by the addition of the known pan HDAC inhibitor LBH -589 (panobinostat) with a final concentration of 1.5 μM. Substrate and product were separated electrophoretically, and fluorescence intensity in the substrate and product peaks were determined and analyzed by Labchip EZ Reader. The reactions were performed in duplicate for each sample. IC50 values were automatically calculated by Origin8 using 4 Parameter Logistic Model. The percent inhibition was plotted against the compound concentration, and the IC50 value was determined from the logistic dose–response curve fitting by Origin 8.0 software.

Mouse Primary Neuronal Histone Acetylation Assays

Mouse primary neuronal cultures were generated in factory precoated poly-d-lysine 96-well plates (BD Biosciences no. BD356692) treated overnight with 75 μL/well of laminin [0.05 mg/mL] (Sigma no. L2020) in PBS buffer. E15 embryonic mouse forebrain was dissociated into a single cell suspension by gentle trituration following trypsin/DNase digestion (trypsin: Cellgro no. 25-052-Cl; DNase: Sigma no. D4527). 12,500 cells per well were plated in 100 μL neurobasal medium (Gibco no. 21103-049) containing 2% B27 (Gibco no. 17504-044) and 1% penicillin/streptomycin/glutamine (Cellgro no. 30-009-CI) and cultured at 37 °C with 5% CO2. After 13 days, cultures were treated with HDAC inhibitors by pin transfer of compound (185 nL per well) using a CyBi-Well vario pinning robot (CyBio Corp., Germany) and subsequently incubated for 24 h at 37 °C with 5% CO2 and then fixed in 4% formaldehyde for 10 min. Following two washes with phosphate-buffered saline, cells were permeabilized and blocked with 0.1% Triton X-100 and 2% BSA in PBS. Cells were stained with an anti-Ac-H4K12 antibody (Millipore, catalog no. 04–119) and Alexa488-conjugated secondary antibody (Molecular Probes). Cell nuclei were identified by staining with Hoechst 33342 (Invitrogen, H3570). Cell nuclei and histone acetylation signal intensity were detected and measured using a laser-scanning microcytometer (Acumen eX3, TTP Laptech). Acumen Explorer software was used to identify a threshold of histone acetylation signal intensity such that, without HDAC inhibitor, >99.5% of cells had intensity levels below the threshold. In the presence of HDAC inhibitors, cells signal intensities above the threshold were scored as “bright green cells” and expressed as a percentage normalized to DMSO controls. EC50 values were determined from curve fitting using GraphPad Prism v5 software (GraphPad Software, Inc. La Jolla, CA, USA).

CNS Target Binding Assay

6 was submitted to a panel of 80 binding assays for common transmembrane and soluble receptors, ion channels, and monoamine transporters in the CNS (High-Throughput Profile P-3, Cerep, France). 6 was assayed in duplicate at 50 nM. This concentration was >10× the IC50 values determined for HDAC targets (0.3–4.1 nM, see Table 2, main text) and in vast excess of the amount of 6 administered in PET imaging experiments. For example, injected dose = 1 mCi/rat; specific activity (see Figure S2) = 1 mCi/1 nmole; therefore, calculated dose = 1 nmole 6/ rat. Inhibition of control binding did not exceed 45% for any target assayed, supporting that 6 predominantly binds HDAC targets.

Radiosynthesis of [11C]6

[11C]CH3I was trapped in a TRACERlab FX-M synthesizer reactor (General Electric) preloaded with a solution of precursor (4) (1.0 mg) in dry DMSO (300 μL). The solution was stirred at 100 °C for 4 min, and water (1.2 mL) was added. The reaction mixture was purified by reverse phase semipreparative HPLC (Phenomenex Luna 5u C8(2), 250 × 10 mm, 5 μm, 5.0 mL/min, 40% H2O + ammonium acetate (0.1 M)/ 60% CH3CN), and the desired fraction was collected. The final product was reformulated by loading onto a solid-phase exchange (SPE) C-18 cartridge, rinsing with 1 M NaOH aq (5 mL), eluting with EtOH (1 mL), and diluting with 50 μL acetic acid in saline (0.9%, 9 mL). The chemical and radiochemical purity of the final product was tested by analytical HPLC (Agilent Eclipse XDB-C18, 150 × 4.6 mm). The identity of the product was confirmed by analytical HPLC with additional co-injection of reference standard. The average time required for the synthesis from end of cyclotron bombardment to end of synthesis was 35 min. The average radiochemical yield was 3–5% (nondecay corrected to trapped [11C]CH3I). Chemical and radiochemical purities were ≥95% with a specific activity 1.0 ± 0.2 Ci/μmol (EOB).

Specific Activity of [11C]6

Specific radioactivity (SA) of [11C]6 was calculated from an analytical HPLC sample of 100 μL. A calibration curve of known mass quantity versus HPLC peak area (254 nm) was used to calculate the mass concentration of the 100 μL. SA was determined using the mass concentration value determined for the formulated [11C]6 solution, volume, and measured radioactivity. The identity of the mass peak assigned to [11C]6 was supported by a second HPLC injection, where [11C]6 was mixed with nonradioactive compound 6 and yielded a single peak. The calibration curve used appears in Figure S1.

Log D Determination

An aliquot (∼50 μL) of the formulated radiotracer was added to a test tube containing 2.5 mL of octanol and 2.5 mL of phosphate buffer solution (pH 7.4).The test tube was mixed by vortex for 2 min and then centrifuged for 2 min to fully separate the aqueous and organic phase. A sample taken from the octanol layer (0.1 mL) and the aqueous layer (1.0 mL) was saved for radioactivity measurement. An additional aliquot of the octanol layer (2.0 mL) was carefully transferred to a new test tube containing 0.5 mL of octanol and 2.5 mL of phosphate buffer solution (pH 7.4). The previous procedure (vortex mixing, centrifugation, sampling, and transfer to the next test tube) was repeated until six sets of aliquot samples had been prepared. The radioactivity of each sample was measured in a well counter (PerkinElmer, Waltham, MA).The log D of each set of samples was derived by the following equation: log D = log (decay-corrected radioactivity in octanol sample × 10/decay-corrected radioactivity in phosphate buffer sample).

Plasma Protein Binding Assay

An aliquot of radiotracer in saline (10 μL) was added to a sample of baboon or human plasma (0.8 mL). The mixture was gently mixed by repeated inversion and incubated for 10 min at room temperature. Following incubation a small sample (20 μL) was removed to determine the total radioactivity in the plasma sample (AT; AT = Abound + Aunbound). An additional 0.2 mL of the plasma sample was placed in the upper compartment of a Centrifree tube (Amicon, Inc., Beverly, MA) and then centrifuged for 10 min. The upper part of the Centrifree tube was discarded, and an aliquot (20 μL) from the bottom part of the tube was removed to determine the amount of radioactivity that passed through the membrane (Aunbound). Plasma protein binding was derived by the following equation: %unbound = Aunbound × 100/AT.

Ex vivo Autoradiography

Twenty μm thick sagittal rat brain sections were cut using a −20 °C cryostat, thaw-mounted onto gelatin-coated slides, fixed in 4% paraformaldehyde containing 2% ethanol for 60 min at 4 °C, and washed 10 min in ice-cold 10 mM Tris-HCl, pH 7.4. Sections were then incubated at room temperature in a 50 mL bath containing either (i) 5% DMSO as control; (ii) unlabeled 6 (100 μM) or (iii) SAHA (100 μM) for 10 min; or (iv) CI-994 (100 μM) for 2 h to allow for slow HDAC binding kinetics known for benzamide compounds including CI-994. All incubation baths contained 10 mM Tris-HCl + 5% DMSO, pH 7.4. [11C]6 was prepared as described, and 100 μCi was added to each bath. Following 10 min incubation at room temperature, sections were washed 2 × 1 min in 10 mM Tris-HCl (pH 7.4) and carefully wiped dry on absorbent towels. Sections were exposed for 1 h to a multisensitive phosphorscreen and developed using a Cyclone Plus phosphorimager (both from PerkinElmer). Resulting parent image was evaluated using ImageJ software (NIH) with JET color lookup table (LUT) with whole-image intensity adjusted to enrich red color in control sections. Individual images of sections were cropped using ImageJ with no additional adjustment to color levels/thresholds.

Rodent PET-CT Acquisition and Post-Processing

Male Sprague–Dawley rats were utilized in pairs, anesthetized with inhalational isoflurane (Forane) at 3% in a carrier of 1.5–2 L/min medical oxygen, and maintained at 2% isoflurane for the duration of the scan. The rats were arranged head-to-head in a Triumph Trimodality PET/CT/SPECT scanner (Gamma Medica, Northridge, CA). Rats were injected standard references or vehicle via a lateral tail vein catheterization at the start of PET acquisition. Dynamic PET acquisition lasted for 60 min and was followed by computed tomography (CT) for anatomic coregistration. PET data were reconstructed using a 3D-MLEM method resulting in a full width at half-maximum (fwhm) resolution of 1 mm. Reconstructed images were exported from the scanner in DICOM format along with an anatomic CT for rodent studies. These files were imported to PMOD (PMOD Technologies, Ltd.) and manually co-registered using six degrees of freedom.

Rodent PET-CT Image Analysis

Volumes of interest (VOIs) were drawn manually as spheres in brain regions guided by high-resolution CT structural images and summed PET data, with a radius no <1 mm to minimize partial volume effects. TACs were exported in terms of decay corrected activity per unit volume at specified time points with gradually increasing intervals. The TACs were expressed as percent injected dose per unit volume for analysis.

Baboon PET-MR Acquisition

Papio anubis baboons, deprived of food for 12 h prior to the study, were included in the PET-MR scans. Atropine 0.05 mg/kg was used intramuscularly to prevent excessive secretion (15 or 30 min of ketamine and Xylazine). Anesthesia was induced with intramuscular xylazine (0.5–2.0 mg/kg) and ketamine (10 mg/kg). After endotracheal intubation, V- and A-lines were inserted, and anesthesia was maintained using isoflurane (1–1.5%, 100% O2 or 50/50 O2/N2O, l L/min). During anesthesia, heart rate, respiration rate, blood pressure, O2 saturation, and end tidal CO2 were monitored. The baboon was catheterized antecubitally for radiotracer injection, and a radial arterial line was placed for metabolite analysis.
Brain imaging
PET-MR images were acquired in a Biograph mMR scanner (Siemens, Munich, Germany) and PET compatible 8-channel coil arrays for nonhuman primate brain imaging with a PET resolution of 5 mm and field of view of 59.4 and 25.8 cm (transaxial and axial, respectively). Dynamic PET image acquisition was initiated followed by administration of the radiotracer in a homogeneous solution of 10% ethanol and 90% isotonic saline. An MEMPRAGE sequence began after 30 min of the baseline scan for anatomic co-registration. To characterize the specific binding of [11C]6, a second imaging experiment was carried out in which unlabeled 6 was co-administered intravenously at the start of acquisition. Both scans were carried out in the same animal on the same day, separated by 2.5 h. In both scans, 4–5 mCi of [11C]6 was administered to the baboon. Dynamic data from the PET scans were recorded in list mode and corrected for attenuation. Baboon data were reconstructed using a 3D-OSEM method resulting in a fwhm resolution of 4 mm.
Body imaging
Simultaneous PET-MR data were acquired using a Siemens Biograph mMR system (Siemens Medical Solutions U.S.A., Inc., Malvern, PA). MR body imaging was performed with real-time respiratory bellows-gating and using the Body Matrix coil and the built-in spine coil as the receiving coil elements. High-resolution anatomical T1W axial, coronal, and sagittal dual-echo scan with the following parameters: TR 115 ms, TE1 1.23 ms, TE2 2.46 ms, matrix size 256 × 168, FOV 35 cm, phase FOV 65.6%) and 4 mm slice thickness were obtained. Additionally, in particular for the purpose of optimal visualization of the pancreas, high-resolution fat-suppressed axial T2W turbo spin echo (TSE) data were obtained with the following parameters: TR 5264 ms, TE 98 ms, matrix size 488 × 235, FOV 18.0 cm, phase FOV 75%, FA 150°, and 3 mm slice thickness. For the purpose of MR-based attenuation correction (MRAC) of the PET data, default T1-weighted (T1W) 2-point Dixon 3D volumetric interpolated breath-hold examination (VIBE) scans were obtained.
PET data were obtained using a single-bed acquisition with an axial field of view of 25.8 cm, transaxial field of view of 59.4 cm, and axial and transaxial resolution of ≤4.8 and ≤4.7 mm, respectively. PET data were acquired dynamically for 80 min after administration of the radiotracer in a homogeneous solution of 10% ethanol and 90% isotonic saline. To characterize the specific binding of [11C]6, a second imaging experiment was carried out in which unlabeled 6 was co-administered intravenously at the start of acquisition. Both scans were carried out in the same animal on the same day, separated by 2.5 h. In both scans, 4–5 mCi of [11C]6 was administered to the baboon. In order to evaluate the blocking of [11C]6 by SAHA, an separate dual-injection study of [11C]6 was performed. In that experiment continuous SAHA infusion (2 mg/mL at 0.16 mL/min) was started after 45 min of baseline scan with [11C]6, and the infusion was continued during the 80 min PET scan after a second injection of [11C]6. In all cases PET data were recorded in list mode, and reconstruction was performed using a 3D-OSEM method resulting in a fwhm resolution of 4 mm. Attenuation correction was performed using the aforementioned 2-point Dixon 3D VIBE MR-derived attenuation maps. Data of each 80 min scan were reconstructed for TAC analysis using the following framing: 12 × 10, 3 × 20, 4 × 30, and 15 × 300 s. For the dedicated self-blocking and SAHA blocking experiments, additional static PET data were reconstructed using data obtained between 40 and 80 min and 20–45 min, respectively, in order to visually display the effects of blocking in multiple organs.

Baboon PET-MR Image Analysis

PET data were motion-corrected, spatially smoothed with a 2.5 mm fwhm Gaussian filter, and registered to the Black baboon brain atlas (43) using JIP tools optimized for nonhuman primate data processing (www.nitrc.org/projects/jip). Image registration was carried out on high-resolution MPRAGE MRI image using a 12 degree of freedom linear algorithm and a nonlinear algorithm to the atlas brain. The transformation was then applied to the simultaneously collected dynamic PET data.
Kinetic modeling was carried out in PMOD (PMOD3.3, PMOD Technologies Ltd., Zurich, Switzerland). VOIs were selected according to the Black baboon brain atlas. A common VOI mask was applied to both baboon scans. TACs were exported from the whole brain, cerebellum, primary motor cortex, putamen, thalamus, primary visual cortex, caudate, and white matter VOIs for analysis. A two-tissue compartmental model was used to estimate regional volume of distribution (VT) with a metabolite-corrected plasma TAC. Voxel-wise VT maps were calculated using a Logan plot from the dynamic PET data. (44) The time until linearity of the plot was achieved and determined for each scan.
In addition, regional K1/k2 and k3/k4 values were also obtained from the baseline scans using a two-tissue compartmental model. It is known thatwith the assumption that Kdapp = 0.4 μM (45) (assumed from ex vivo HDAC-complex Kd measure for SAHA, which exhibits a similar IC50 in in vitro activity-based assays we determined). Averaged Bmax from the selected VOIs was estimated to be 19.6 ± 2.9 μM (mean ± SD).

Plasma and Metabolite Analysis

Arterial samples collected during imaging from the baboon were centrifuged to obtain plasma, which was then removed and placed in an automated gamma counter that was calibrated to the PET scanner. Metabolite analysis was conducted on a custom automated robot fitted with Phenomenex SPE Strata-X 500 mg solid phase extraction cartridges that were primed with ethanol (2 mL) and deionized water (20 mL). Protein precipitation was achieved by addition of plasma (300 μL) to acetonitrile (300 μL), which was centrifuged for 1 min to obtain protein-free plasma (PFP). 300 μL of PFP/acetonitrile solution was diluted into deionized water (3 mL), loaded onto the C18 cartridge, and removed of polar metabolites with 100% water. Next, a series of extractions were performed using water and acetonitrile in quantities: 95:5, 90:10, 85:15, 80:20, 70:30, 60:40, 30:70, and 100% acetonitrile at a volume of 4 mL. A control experiment was performed before metabolite analysis to determine the retention of the parent compound by injection of a small amount of [11C]6 onto a test series of extraction cartridges. Each sample was counted in a WIZARD2 Automatic Gamma Counter to determine the presence of radiolabeled metabolites.

Brain Metabolite Analysis

One rat under pentobarbital anesthesia (50 mg/kg, ip) was administered 0.538 mCi of [11C]6 by tail vein injection in 0.7 mL and after 30 min, sacrificed by pentobarbital overdose (additional 150 mg/kg, ip), and followed by rapid decapitation. The brain was removed, sagitally hemisected, and homogenized in 2 mL acetonitrile. The resulting suspension was centrifuged at 1500 rpm for 5 min, and 0.6 mL of clear supernatant was vortexed with 3 mL water and applied to Phenomenex SPE Strata-X 500 mg solid phase extraction cartridges, washed, and fractionally eluted with water containing increasing proportions of acetonitrile (100:0, 95:5, 90:10, 85:15, 80:20, 70:30, 60:40, 30:70, 0:100). Each sample was counted in a WIZARD2 Automatic Gamma Counter to determine the presence of radiolabeled metabolites.

Supporting Information

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The results of off-target binding, mPET imaging in rodents and SAHA pretreated study in NHP were shown in Table S1, Figure S1–S6. This material is available free of charge via the Internet at http://pubs.acs.org.

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Author Information

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  • Corresponding Author
    • 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;  Email: [email protected]
  • Authors
    • Changning Wang - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 73 High Street, Charlestown, Massachusetts 02129, United States
    • Frederick A. Schroeder - 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
    • Hsiao-Ying Wey - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 73 High Street, Charlestown, Massachusetts 02129, United States
    • Ronald Borra - Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 73 High Street, Charlestown, Massachusetts 02129, United States
    • Florence F. Wagner - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States
    • Surya Reis - Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States
    • Sung Won Kim - Laboratory of Neuroimaging, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892, United States
    • Edward B. Holson - Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, Massachusetts 02142, United States
    • Stephen J. Haggarty - Chemical Neurobiology Laboratory, Departments of Neurology and Psychiatry, Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgment

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C.W. and H.Y.W. are supported by the Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430). Research was supported by the National Institute of Drug Abuse (NIDA) of the National Institutes of Health under grant numbers R01DA030321 (J.M.H.; S.J.H) with additional support under grant R01DA028301 (S.J.H.). This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at the Massachusetts General Hospital, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Regional Resource supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health. This work also involved the use of instrumentation supported by the NIH Shared Instrumentation Grant Program and/or High-End Instrumentation Grant Program; specifically, grant nos: S10RR017208, S10RR026666, S10RR022976, S10RR019933, and S10RR029495. The authors are grateful to Joe Mandeville and Helen Deng as well as the Martinos Center radiopharmacy and imaging staff (Grae Arabasz, Shirley Hsu, Stephen Carlin, Chris Moseley, Nathan Schauer, Ehimen Aisaborhale, Judit Sore) for help with nonhuman primate experiments. HDAC activity screening was enabled by a Caliper assay developed by Jennifer Gale and Yan-Ling Zhang at the Broad Institute.

Abbreviations Used

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HDACs

histone deacetylases

CNS

Center for Nanoscale Systems

PET

positron emission tomography

PPB

plasma protein binding

DAT

dopamine transporter

P-gp

P-glycoprotein

NHP

nonhuman primate

GWAS

genome-wide association studies

SNPs

single nucleotide polymorphisms

tPSA

total polar surface area

TAC

time–activity curve

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    Graff Johannes; Rei Damien; Guan Ji-Song; Wang Wen-Yuan; Seo Jinsoo; Hennig Krista M; Nieland Thomas J F; Fass Daniel M; Kao Patricia F; Kahn Martin; Su Susan C; Samiei Alireza; Joseph Nadine; Haggarty Stephen J; Delalle Ivana; Tsai Li-Huei
    Nature (2012), 483 (7388), 222-6 ISSN:.
    Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
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  5. 5
    Zhang, L.; Sheng, S.; Qin, C. The role of HDAC6 in Alzheimer’s disease J. Alzheimer’s Dis. 2013, 33, 283– 295
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    5
    The Role of HDAC6 in Alzheimer's Disease
    Zhang, Ling; Sheng, Shuli; Qin, Chuan
    Journal of Alzheimer's Disease (2013), 33 (2), 283-295CODEN: JADIF9; ISSN:1387-2877. (IOS Press)
    A review. The expression of histone deacetylase 6 (HDAC6)-a versatile enzyme with a known role in epigenetics-increases significantly in the hippocampus and other relevant brain regions in both patients with Alzheimer's disease (AD) and animal models of AD. However, when and how HDAC6 expression increases during the course of AD progression remains unclear. Whether HDAC6 overexpression is an underlying cause of AD or a condition resulting from AD is controversial. Mounting evidence suggests that increased HDAC6 expression contributes to AD-assocd. neurodegeneration, although beneficial effects have also been identified. This review article addresses recent research on HDAC6 structure and function, and highlights the potential detrimental and protective roles of HDAC6 overexpression in AD. We hope to shed light on whether HDAC6 overexpression is assocd. with AD etiopathogenesis or whether it rescues AD-assocd. neurodegeneration compensatorily. Furthermore, we discuss new evidence showing that HDAC6 may be a therapeutic target for AD.
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  6. 6
    Jakovcevski, M.; Bharadwaj, R.; Straubhaar, J.; Gao, G.; Gavin, D. P.; Jakovcevski, I.; Mitchell, A. C.; Akbarian, S. Prefrontal cortical dysfunction after overexpression of histone deacetylase 1 Biol. Psychiatry 2013, 74, 696– 705
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    6
    Prefrontal Cortical Dysfunction After Overexpression of Histone Deacetylase 1
    Jakovcevski, Mira; Bharadwaj, Rahul; Straubhaar, Juerg; Gao, Guangping; Gavin, David P.; Jakovcevski, Igor; Mitchell, Amanda C.; Akbarian, Schahram
    Biological Psychiatry (2013), 74 (9), 696-705CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
    Background: Postmortem brain studies have shown that HDAC1-a lysine deacetylase with broad activity against histones and nonhistone proteins-is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior. Methods: Using adeno-assocd. virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine. Results: Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA-DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) down-regulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts. Conclusions: Excessive HDAC1 activity, due to developmental defects or other factors, is assocd. with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC.
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  7. 7
    Morris, M. J.; Mahgoub, M.; Na, E. S.; Pranav, H.; Monteggia, L. M. Loss of histone deacetylase 2 improves working memory and accelerates extinction learning J. Neurosci. 2013, 33, 6401– 6411
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    7
    Loss of histone deacetylase 2 improves working memory and accelerates extinction learning
    Morris, Michael J.; Mahgoub, Melissa; Na, Elisa S.; Pranav, Heena; Monteggia, Lisa M.
    Journal of Neuroscience (2013), 33 (15), 6401-6411CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacol. inhibition of histone deacetylases (HDACs) improves performance in learning tasks; however, many of these classical agents are "pan-HDAC" inhibitors, and their use makes it difficult to det. the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity. We show that selective knock-out of Hdac2 led to a robust acceleration of the extinction rate of conditioned fear responses and a conditioned taste aversion as well as enhanced performance in an attentional set-shifting task. Hdac2 knock-out had no impact on episodic memory or motor learning, suggesting that the effects are task-dependent, with the predominant impact of HDAC2 inhibition being an enhancement in an animal's ability to rapidly adapt its behavioral strategy as a result of changes in associative contingencies. Our results demonstrate that the loss of HDAC2 improves associative learning, with no effect in nonassociative learning tasks, suggesting a specific role for HDAC2 in particular types of learning. HDAC2 may be an intriguing target for cognitive and psychiatric disorders that are characterized by an inability to inhibit behavioral responsiveness to maladaptive or no longer relevant assocns.
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  8. 8
    Cao, D. J.; Wang, Z. V.; Battiprolu, P. K.; Jiang, N.; Morales, C. R.; Kong, Y.; Rothermel, B. A.; Gillette, T. G.; Hill, J. A. Histone deacetylase (HDAC) inhibitors attenuate cardiac hypertrophy by suppressing autophagy Proc. Natl. Acad. Sci. U.S.A. 2011, 108, 4123– 4128
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  9. 9
    Ferguson, B. S.; Harrison, B. C.; Jeong, M. Y.; Reid, B. G.; Wempe, M. F.; Wagner, F. F.; Holson, E. B.; McKinsey, T. A. Signal-dependent repression of DUSP5 by class I HDACs controls nuclear ERK activity and cardiomyocyte hypertrophy Proc. Natl. Acad. Sci. U.S.A. 2013, 110, 9806– 9811
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  10. 10
    Barnes, P. J. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease J. Allergy. Clin. Immunol. 2013, 131, 636– 645
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    10
    Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease
    Barnes, Peter J.
    Journal of Allergy and Clinical Immunology (2013), 131 (3), 636-645CODEN: JACIBY; ISSN:0091-6749. (Elsevier)
    A review. Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The mol. mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several mol. mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the mol. mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.
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  11. 11
    Brochier, C.; Dennis, G.; Rivieccio, M. A.; McLaughlin, K.; Coppola, G.; Ratan, R. R.; Langley, B. Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons J. Neurosci. 2013, 33, 8621– 8632
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    11
    Specific acetylation of p53 by HDAC inhibition prevents DNA damage-induced apoptosis in neurons
    Brochier, Camille; Dennis, Gretel; Rivieccio, Mark A.; McLaughlin, Kathryn; Coppola, Giovanni; Ratan, Rajiv R.; Langley, Brett
    Journal of Neuroscience (2013), 33 (20), 8621-8632CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
    Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurol. dysfunction in a host of neurodegenerative disease models. The precise mol. mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes. Specifically, we identify that acetylation at K382 and K381 prevents p53 from assocg. with the pro-apoptotic PUMA gene promoter, activating transcription, and inducing apoptosis in mouse primary cortical neurons. Paradoxically, acetylation of p53 at the same lysines in various cancer cell lines leads to the induction of PUMA expression and death. Together, our data provide a mol. understanding of the specific outcomes of HDAC inhibition and suggest that strategies aimed at enhancing p53 acetylation at K381 and K382 might be therapeutically viable for capturing the beneficial effects in the CNS, without compromising tumor suppression.
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  12. 12
    Zhang, Z.; Yamashita, H.; Toyama, T.; Sugiura, H.; Omoto, Y.; Ando, Y.; Mita, K.; Hamaguchi, M.; Hayashi, S.; Iwase, H. HDAC6 expression is correlated with better survival in breast cancer Clin. Cancer Res. 2004, 10, 6962– 6968
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    12
    HDAC6 expression is correlated with better survival in breast cancer
    Zhang, Zhenhuan; Yamashita, Hiroko; Toyama, Tatsuya; Sugiura, Hiroshi; Omoto, Yoko; Ando, Yoshiaki; Mita, Keiko; Hamaguchi, Maho; Hayashi, Shin-ichi; Iwase, Hirotaka
    Clinical Cancer Research (2004), 10 (20), 6962-6968CODEN: CCREF4; ISSN:1078-0432. (American Association for Cancer Research)
    The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. In the present study, the level of HDAC6 mRNA expression was analyzed with quant. real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also detd. by immunohistochem. An assocn. was sought between HDAC6 expression and various clinicopathol. factors. HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histol. grade, and in estrogen receptor α- and progesterone receptor-pos. tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathol. factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate anal. failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathol. factors. We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Addnl. investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.
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    Rajendran, P.; Kidane, A. I.; Yu, T. W.; Dashwood, W. M.; Bisson, W. H.; Lohr, C. V.; Ho, E.; Williams, D. E.; Dashwood, R. H. HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates Epigenetics 2013, 8, 612– 623
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  14. 14
    Cai, Y.; Geutjes, E. J.; de Lint, K.; Roepman, P.; Bruurs, L.; Yu, L. R.; Wang, W.; van Blijswijk, J.; Mohammad, H.; de Rink, I.; Bernards, R.; Baylin, S. B. The NuRD complex cooperates with DNMTs to maintain silencing of key colorectal tumor suppressor genes Oncogene 2014, 33, 2157– 2168
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  15. 15
    Kim, M. G.; Pak, J. H.; Choi, W. H.; Park, J. Y.; Nam, J. H.; Kim, J. H. The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines J. Gynecol. Oncol. 2012, 23, 182– 189
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    15
    The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines
    Kim, Min-Gyun; Pak, Jhang Ho; Choi, Won Ho; Park, Jeong-Yeol; Nam, Joo-Hyun; Kim, Jong-Hyeok
    Journal of Gynecologic Oncology (2012), 23 (3), 182-189CODEN: JGOOAH; ISSN:2005-0380. (Korean Society of Gynecologic Oncology and Colposcopy)
    Objective: To investigate the relationship between cisplatin resistance and histone deacetylase (HDAC) isoform overexpression in ovarian cancer cell lines. Methods: Expression of four HDAC isoforms (HDAC 1, 2, 3, and 4) in two ovarian cancer cell lines, SKOV3 and OVCAR3, exposed to various concns. of cisplatin was examd. by western blot analyses. Cells were transfected with plasmid DNA of each HDAC. The overexpression of protein and mRNA of each HDAC was confirmed by western blot and reverse transcriptase-polymerase chain reaction analyses, resp. The cell viability of the SKOV3 and OVCAR3 cells transfected with HDAC plasmid DNA was measured using the cell counting kit-8 assay after treatment with cisplatin. Results: The 50% inhibitory concn. of the SKOV3 and OVCAR3 cells can be detd. 15-24 h after treatment with 15 μg/mL cisplatin. The expression level of acetylated histone 3 protein in SKOV3 cells increased after exposure to cisplatin. Compared with control cells at 24 h after cisplatin exposure, the viability of SKOV3 cells overexpressing HDAC 1 and 3 increased by 15% and 13% (p<0.05), resp. On the other hand, OVCAR3 cells that overexpressed HDAC 2 and 4 exhibited increased cell viability by 23% and 20% (p<0.05), resp., compared with control cells 24 h after exposure to cisplatin. Conclusion: In SKOV3 and OVCAR3 epithelial ovarian cancer cell lines, the correlation between HDAC overexpression and cisplatin resistance was confirmed. However, the specific HDAC isoform assocd. with resistance to cisplatin varied depending on the ovarian cancer cell line. These results may suggest that each HDAC isoform conveys cisplatin resistance via different mechanisms.
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  16. 16
    Hayashi, A.; Horiuchi, A.; Kikuchi, N.; Hayashi, T.; Fuseya, C.; Suzuki, A.; Konishi, I.; Shiozawa, T. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin Int. J. Cancer. 2010, 127, 1332– 1346
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    16
    Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin
    Hayashi, Akiko; Horiuchi, Akiko; Kikuchi, Norihiko; Hayashi, Takuma; Fuseya, Chiho; Suzuki, Akihisa; Konishi, Ikuo; Shiozawa, Tanri
    International Journal of Cancer (2010), 127 (6), 1332-1346CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
    Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examd. the immunohistochem. expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathol. parameters. In addn., we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related mols. and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochem. expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examd., only HDAC1 was assocd. with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in assocn. with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.
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  17. 17
    Benes, F. M.; Lim, B.; Matzilevich, D.; Walsh, J. P.; Subburaju, S.; Minns, M. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 10164– 10169
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  18. 18
    Broide, R. S.; Redwine, J. M.; Aftahi, N.; Young, W.; Bloom, F. E.; Winrow, C. J. Distribution of histone deacetylases 1–11 in the rat brain J. Mol. Neurosci. 2007, 31, 47– 58
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    18
    Distribution of histone deacetylases 1-11 in the rat brain
    Broide, Ron S.; Redwine, Jeff M.; Aftahi, Najla; Young, Warren; Bloom, Floyd E.; Winrow, Christopher J.
    Journal of Molecular Neuroscience (2007), 31 (1), 47-58CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)
    Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling mols. is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyltransferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurodegeneration. The authors initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resoln. in situ hybridization (ISH) and imaging technol. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addn., immunohistochem. was performed on these samples to sep. examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled stds. and thereby enabled semiquant. anal. of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examg. the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
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  19. 19
    Hooker, J. M.; Kim, S. W.; Alexoff, D.; Xu, Y.; Shea, C.; Reid, A.; Volkow, N.; Fowler, J. S. Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [11C]MS-275 using Positron Emission Tomography ACS Chem. Neurosci. 2010, 1, 65– 73
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    19
    Histone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [11C]MS-275 using Positron Emission Tomography
    Hooker, Jacob M.; Kim, Sung Won; Alexoff, David; Xu, Youwen; Shea, Colleen; Reid, Alicia; Volkow, Nora; Fowler, Joanna S.
    ACS Chemical Neuroscience (2010), 1 (1), 65-73CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    MS-275 (entinostat) is a histone deacetylase (HDAC) inhibitor currently in clin. trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood-brain barrier (BBB) and cause region-specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomog. (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we detd. that [11C]MS-275 has low uptake in brain tissue when administered i.v. to nonhuman primates. In rodent studies, we obsd. that pharmacokinetics and brain accumulation of [11C]MS-275 were not changed by the coadministration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compds. for peripheral cancer treatment (where CNS exclusion is often advantageous) but also for the treatment of neurol. disorders (where CNS penetration is crit.).
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  20. 20
    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.; Nishi, R.; Mizuma, H.; Onoe, H.; Kagawa, S.; Higashi, T.; Fukumitsu, N.; Alauddin, M.; Tong, W.; Herholz, K.; Gelovani, J. G. Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with (1)(8)F-FAHA Neuroimage 2013, 64, 630– 639
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  21. 21
    Hendricks, J. A.; Keliher, E. J.; Marinelli, B.; Reiner, T.; Weissleder, R.; Mazitschek, R. In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA) J. Med. Chem. 2011, 54, 5576– 5582
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  22. 22
    Seo, Y. J.; Kang, Y.; Muench, L.; Reid, A.; Caesar, S.; Jean, L.; Fevier-Wagner, F.; Holson, E. B.; Haggarty, S. J.; Weiss, P.; King, P.; Carter, P.; Volkow, N. D.; Fowler, J. S.; Hooker, J. M.; Kim, S. W. Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors ACS Chem. Neurosci. 2014, 5, 588– 596
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    22
    Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors
    Seo, Young Jun; Kang, Yeona; Muench, Lisa; Reid, Alicia; Caesar, Shannon; Jean, Logan; Wagner, Florence; Holson, Edward; Haggarty, Stephen J.; Weiss, Philipp; King, Payton; Carter, Pauline; Volkow, Nora D.; Fowler, Joanna S.; Hooker, Jacob M.; Kim, Sung Won
    ACS Chemical Neuroscience (2014), 5 (7), 588-596CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addn. to low HDAC potency and selectivity obsd., poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here the authors report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compds. based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compd. to feed back into the design process. A total of 17 compds. were evaluated, revealing mols. with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivs. exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivs. showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate mols. for small mol. probes and drugs.
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  23. 23
    Seo, Y. J.; Muench, L.; Reid, A.; Chen, J.; Kang, Y.; Hooker, J. M.; Volkow, N. D.; Fowler, J. S.; Kim, S. W. Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain Bioorg. Med. Chem. Lett. 2013, 23, 6700– 6705
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    Hanson, J. E.; La, H.; Plise, E.; Chen, Y. H.; Ding, X.; Hanania, T.; Sabath, E. V.; Alexandrov, V.; Brunner, D.; Leahy, E.; Steiner, P.; Liu, L.; Scearce-Levie, K.; Zhou, Q. SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition PLoS One 2013, 8, e69964
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    Maugh, T. H., 2nd Panel urges wide use of antiviral drug Science 1979, 206, 1058– 1060
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    Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse ACS Chem. Neurosci. 2013, 4, 1081– 1092
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    The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse
    Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael
    ACS Chemical Neuroscience (2013), 4 (7), 1081-1092CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
    Two novel adamantane derivs., adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the prepn. of AB-001, SDB-001, and several analogs intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogs govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compds. showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ9-tetrahydrocannabinol (Δ9-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Addnl., the changes in body temp. and heart rate affected by SDB-001 are of longer duration than those of Δ9-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homolog, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ9-THC, JWH-018, and SDB-001.
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    Gopalan, B.; Ponpandian, T.; Kachhadia, V.; Bharathimohan, K.; Vignesh, R.; Sivasudar, V.; Narayanan, S.; Mandar, B.; Praveen, R.; Saranya, N.; Rajagopal, S. Discovery of adamantane based highly potent HDAC inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 2532– 2537
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    Farde, L.; Eriksson, L.; Blomquist, G.; Halldin, C. Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET--a comparison to the equilibrium analysis J. Cereb. Blood Flow Metab. 1989, 9, 696– 708
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    Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET - a comparison to the equilibrium analysis
    Farde, L.; Eriksson, L.; Blomquist, G.; Halldin, C.
    Journal of Cerebral Blood Flow and Metabolism (1989), 9 (5), 696-708CODEN: JCBMDN; ISSN:0271-678X.
    [11C]raclopride binding to central D2-dopamine receptors in humans has previously been examd. by positron emission tomog. (PET). Based on the rapid occurrence of binding equil., a satn. anal. was developed for the detn. of receptor d. (Bmax) and affinity (Kd). For anal. of PET measurements obtained with other ligands, a kinetic 3-compartment model was used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equil. anal. to data obtained from 4 PET expts. in each of 3 healthy subjects. First regional cerebral blood vol. was detd. In the second and third expt., [11C]raclopride with high and low specific activity was used. In a fourth expt., the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concn. of free radioligand and nonspecific binding in brain. Radioactivity in arterial blood was measured using an automated blood sampling system. Bmax And Kd values for [11C]raclopride binding could be detd. also with the kinetic anal. As expected theor., those values were similar to those obtained with the equil. anal. In addn., the kinetic anal. allowed sep. detn. of the assocn. and dissocn. rate consts., kon and koff, resp. Examn. of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.
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  29. 29
    Innis, R. B.; Cunningham, V. J.; Delforge, J.; Fujita, M.; Gjedde, A.; Gunn, R. N.; Holden, J.; Houle, S.; Huang, S. C.; Ichise, M.; Iida, H.; Ito, H.; Kimura, Y.; Koeppe, R. A.; Knudsen, G. M.; Knuuti, J.; Lammertsma, A. A.; Laruelle, M.; Logan, J.; Maguire, R. P.; Mintun, M. A.; Morris, E. D.; Parsey, R.; Price, J. C.; Slifstein, M.; Sossi, V.; Suhara, T.; Votaw, J. R.; Wong, D. F.; Carson, R. E. Consensus nomenclature for in vivo imaging of reversibly binding radioligands J. Cereb. Blood Flow Metab. 2007, 27, 1533– 1539
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    Consensus nomenclature for in vivo imaging of reversibly binding radioligands
    Innis, Robert B.; Cunningham, Vincent J.; Delforge, Jacques; Fujita, Masahiro; Gjedde, Albert; Gunn, Roger N.; Holden, James; Houle, Sylvain; Huang, Sung-Cheng; Ichise, Masanori; Iida, Hidehiro; Ito, Hiroshi; Kimura, Yuichi; Koeppe, Robert A.; Knudsen, Gitte M.; Knuuti, Juhani; Lammertsma, Adriaan A.; Laruelle, Marc; Logan, Jean; Maguire, Ralph Paul; Mintun, Mark A.; Morris, Evan D.; Parsey, Ramin; Price, Julie C.; Slifstein, Mark; Sossi, Vesna; Suhara, Tetsuya; Votaw, John R.; Wong, Dean F.; Carson, Richard E.
    Journal of Cerebral Blood Flow & Metabolism (2007), 27 (9), 1533-1539CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)
    A review. An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo mol. imaging of reversibly binding radioligands.
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    Wang, Y.; Zhang, Y. L.; Hennig, K.; Gale, J. P.; Hong, Y.; Cha, A.; Riley, M.; Wagner, F.; Haggarty, S. J.; Holson, E.; Hooker, J. Class I HDAC imaging using [ (3)H]CI-994 autoradiography Epigenetics 2013, 8, 756– 764
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    Schroeder, F. A.; Lewis, M. C.; Fass, D. M.; Wagner, F. F.; Zhang, Y. L.; Hennig, K. M.; Gale, J.; Zhao, W. N.; Reis, S.; Barker, D. D.; Berry-Scott, E.; Kim, S. W.; Clore, E. L.; Hooker, J. M.; Holson, E. B.; Haggarty, S. J.; Petryshen, T. L. A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests PLoS One 2013, 8, e71323
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    Fass, D. M.; Schroeder, F. A.; Perlis, R. H.; Haggarty, S. J. Epigenetic mechanisms in mood disorders: Targeting neuroplasticity Neuroscience 2014, 264, 112– 130
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    Davies, G.; Tenesa, A.; Payton, A.; Yang, J.; Harris, S. E.; Liewald, D.; Ke, X.; Le Hellard, S.; Christoforou, A.; Luciano, M.; McGhee, K.; Lopez, L.; Gow, A. J.; Corley, J.; Redmond, P.; Fox, H. C.; Haggarty, P.; Whalley, L. J.; McNeill, G.; Goddard, M. E.; Espeseth, T.; Lundervold, A. J.; Reinvang, I.; Pickles, A.; Steen, V. M.; Ollier, W.; Porteous, D. J.; Horan, M.; Starr, J. M.; Pendleton, N.; Visscher, P. M.; Deary, I. J. Genome-wide association studies establish that human intelligence is highly heritable and polygenic Mol. Psychiatry 2011, 16, 996– 1005
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    Genome-wide association studies establish that human intelligence is highly heritable and polygenic
    Davies, G.; Tenesa, A.; Payton, A.; Yang, J.; Harris, S. E.; Liewald, D.; Ke, X.; Le Hellard, S.; Christoforou, A.; Luciano, M.; McGhee, K.; Lopez, L.; Gow, A. J.; Corley, J.; Redmond, P.; Fox, H. C.; Haggarty, P.; Whalley, L. J.; McNeill, G.; Goddard, M. E.; Espeseth, T.; Lundervold, A. J.; Reinvang, I.; Pickles, A.; Steen, V. M.; Ollier, W.; Porteous, D. J.; Horan, M.; Starr, J. M.; Pendleton, N.; Visscher, P. M.; Deary, I. J.
    Molecular Psychiatry (2011), 16 (10), 996-1005CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
    General intelligence is an important human quant. trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly assocd. with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. The authors conducted a genome-wide anal. of 3511 unrelated adults with data on 549 692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. They est. that 40% of the variation in crystd.-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequil. between genotyped common SNP markers and unknown causal variants. These ests. provide lower bounds for the narrow-sense heritability of the traits. The authors partitioned genetic variation on individual chromosomes and found that, on av., longer chromosomes explain more variation. Finally, using just SNP data the authors predicted ∼1% of the variance of crystd. and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, resp.). These results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence. Mol. Psychiatry (2011) 16, 996-1005; doi:10.1038/mp.2011.85; published online 9 August 2011.
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    McPherson, R. From genome-wide association studies to functional genomics: new insights into cardiovascular disease Can. J. Cardiol. 2013, 29, 23– 29
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    From genome-wide association studies to functional genomics: new insights into cardiovascular disease
    McPherson Ruth
    The Canadian journal of cardiology (2013), 29 (1), 23-9 ISSN:.
    Genome-wide association studies (GWASs) for coronary artery disease (CAD) have identified more than 30 variants robustly associated with CAD risk. The majority are not associated with conventional risk factors but highlight novel pathways, including cellular proliferation. Although some risk variants are nonsynonymous coding variants resulting in an amino acid change in the encoded protein, the majority are in noncoding regions of the genome and may encompass multiple signals of variable effect. The use of genetic data for development of new therapies requires the identification of causative genetic variants and elucidation of the molecular mechanisms by which they predispose to CAD. The computational and laboratory approaches for the interpretation of GWAS data are discussed with a particular focus on noncoding variants, including the study of regulatory elements, the evaluation of nonsynonymous coding variants, and expression quantitative trait locus analysis for the integration of GWAS data with genome-wide messenger RNA expression data.
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    Torres, J. M.; Cox, N. J.; Philipson, L. H. Genome wide association studies for diabetes: perspective on results and challenges Pediatr. Diabetes 2013, 14, 90– 96
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    Genome wide association studies for diabetes: perspective on results and challenges
    Torres, J. M.; Cox, N. J.; Philipson, L. H.
    Pediatric Diabetes (2013), 14 (2), 90-96CODEN: PDEIBT; ISSN:1399-5448. (Wiley-Blackwell)
    A review. Recent results of genome wide assocn. study (GWAS) for diabetes genes, while reaching impressive tech. milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clin. utility. The relative risk assocd. with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a phys. exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known assocns., and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quant. traits are likely to yield even more insights.
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    Mells, G. F.; Kaser, A.; Karlsen, T. H. Novel insights into autoimmune liver diseases provided by genome-wide association studies J. Autoimmun. 2013, 46, 41– 54
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    Novel insights into autoimmune liver diseases provided by genome-wide association studies
    Mells, George F.; Kaser, Arthur; Karlsen, Tom H.
    Journal of Autoimmunity (2013), 46 (), 41-54CODEN: JOAUEP; ISSN:0896-8411. (Elsevier Ltd.)
    A review. Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify mol. targets for pharmacotherapy. Early genetic studies consisted of HLA assocn. studies and non-HLA candidate gene assocn. studies, designed to identify assocn. with selected HLA or non-HLA loci. HLA assocn. studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak assocns. detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide assocn. studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clin. conditions. The specific genetic basis of these PBC and PSC assocd. inflammatory themes as detd. by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.
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    Bowcock, A. M. Genome-wide association studies and infectious disease Crit. Rev. Immunol. 2010, 30, 305– 309
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    37
    Genome-wide association studies and infectious disease
    Bowcock, Anne M.
    Critical Reviews in Immunology (2010), 30 (3), 305-309CODEN: CCRIDE; ISSN:1040-8401. (Begell House, Inc.)
    A review. The identification of genetic variants predisposing to complex diseases and phenotypes represent a challenge for geneticists in the early part of the 21st century. These are not simple Mendelian disorders caused by single mutations, such as cystic fibrosis or Huntington's disease, but common diseases that are usually polygenic in origin. The predisposing genes can be susceptibility factors or protective factors. One example of such a complex disease is the inflammatory skin disease psoriasis. However, another example could be protection from an infectious disease. Both of these phenotypes are due in part to the presence of low-risk variants in the host. Moreover, all of these complex phenotypes require environmental triggers as well and, in the case of infectious diseases, these are pathogens. In the case of other common diseases such as cardiovascular disease the triggers are often lifestyle-related issues such as diet or exercise. Genome-wide assocn. studies are now identifying some of these genetic susceptibility factors.
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  38. 38
    Xu, C.; Aragam, N.; Li, X.; Villla, E. C.; Wang, L.; Briones, D.; Petty, L.; Posada, Y.; Arana, T. B.; Cruz, G.; Mao, C.; Camarillo, C.; Su, B. B.; Escamilla, M. A.; BCL9, Wang K. and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies PLoS One 2013, 8, e51674
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    Wang, C.; Schroeder, F. A.; Hooker, J. M. Visualizing epigenetics: Current advances and advantages in HDAC PET imaging techniques Neuroscience 2014, 264, 186– 197
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    Tang, J.; Yan, Y.; Zhao, T. C.; Gong, R.; Bayliss, G.; Yan, H.; Zhuang, S.; Class, I. HDAC activity is required for renal protection and regeneration after acute kidney injury Am. J. Physiol. Renal Physiol. 2014, 307, F303– 16
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    Schroeder, F. A.; Lin, C. L.; Crusio, W. E.; Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse Biol. Psychiatry 2007, 62, 55– 64
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    41
    Antidepressant-Like Effects of the Histone Deacetylase Inhibitor, Sodium Butyrate, in the Mouse
    Schroeder, Frederick A.; Lin, Cong Lily; Crusio, Wim E.; Akbarian, Schahram
    Biological Psychiatry (2007), 62 (1), 55-64CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)
    Chromatin remodeling, including changes in histone acetylation, might play a role in the pathophysiol. and treatment of depression. We investigated whether the histone deacetylase inhibitor sodium butyrate (SB) administered as single drug or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine exerts antidepressant-like effects in mice. Mice (C57BL/6J) received injections of SB, fluoxetine, or a combination of both drugs either acutely or chronically for a period of 28 days and were subjected to a battery of tests to measure anxiety and behavioral despair. Histone acetylation and expression of brain-derived neurotrophic factor (BDNF) were monitored in hippocampus and frontal cortex. Co-treatment with SB and fluoxetine resulted in a significant 20-40% decrease in immobility scores in the tail suspension test (TST), a measure for behavioral despair, both acutely and chronically. In contrast, decreased immobility after single drug regimens was limited either to the acute (fluoxetine) or chronic (SB) paradigm. Systemic injection of SB induced short-lasting histone hyperacetylation in hippocampus and frontal cortex. Among the four treatment paradigms that resulted in improved immobility scores in the TST, three were assocd. with a transient, at least 50% increase in BDNF transcript in frontal cortex, whereas changes in hippocampus were less consistent. The histone deacetylase inhibitor SB exerts antidepressant-like effects in the mouse. The therapeutic benefits and mol. actions of histone modifying drugs, including co-treatment with SSRIs and other newer generation antidepressant medications, warrant further exploration in exptl. models.
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    Reid, A. E.; Hooker, J.; Shumay, E.; Logan, J.; Shea, C.; Kim, S. W.; Collins, S.; Xu, Y.; Volkow, N.; Fowler, J. S. Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain Nucl. Med. Biol. 2009, 36, 247– 258
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    42
    Evaluation of 6-([18F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain
    Reid, Alicia E.; Hooker, Jacob; Shumay, Elena; Logan, Jean; Shea, Colleen; Kim, Sung Won; Collins, Shanika; Xu, Youwen; Volkow, Nora; Fowler, Joanna S.
    Nuclear Medicine and Biology (2009), 36 (3), 247-258CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
    Introduction: Histone deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) for positron emission tomog. imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [18F]fluoroacetate ([18F]FAC). Methods: [18F]FAHA and its metabolite [18F]FAC were prepd., and their in vivo biodistribution and pharmacokinetics were detd. in baboons. [18F]FAHA metab. and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chem. form of F-18 in rodent brain was assessed by ex vivo studies. Distribution vols. for [18F]FAHA in the brain were derived. Results: [18F]FAHA was rapidly metabolized to [18F]FAC, and both labeled compds. entered the brain. [18F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [18F]FAC showed little variation in regional brain uptake and kinetics. A kinetic anal. that takes into account the uptake of peripherally produced [18F]FAC indicated that SAHA inhibited binding of [18F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metab. of [18F]FAHA to [18F]FAC within the cell and diffusion of [18F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [18F]FAC at 7 min postinjection of [18F]FAHA. Conclusion: The rapid metab. of [18F]FAHA to [18F]FAC in the periphery complicates the quant. anal. of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [18F]FAHA in the brain was obsd. Validating the nature of this interaction as HDAC specific will require addnl. studies.
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    Black, K. J.; Koller, J. M.; Snyder, A. Z.; Perlmutter, J. S. Atlas template images for nonhuman primate neuroimaging: baboon and macaque Methods Enzymol. 2004, 385, 91– 102
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    Logan, J.; Fowler, J. S.; Volkow, N. D.; Wang, G. J.; Ding, Y. S.; Alexoff, D. L. Distribution volume ratios without blood sampling from graphical analysis of PET data J. Cereb. Blood Flow Metab. 1996, 16, 834– 840
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    44
    Distribution volume ratios without blood sampling from graphical analysis of PET data
    Logan J; Fowler J S; Volkow N D; Wang G J; Ding Y S; Alexoff D L
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1996), 16 (5), 834-40 ISSN:0271-678X.
    The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.
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    Bantscheff, M.; Hopf, C.; Savitski, M. M.; Dittmann, A.; Grandi, P.; Michon, A. M.; Schlegl, J.; Abraham, Y.; Becher, I.; Bergamini, G.; Boesche, M.; Delling, M.; Dumpelfeld, B.; Eberhard, D.; Huthmacher, C.; Mathieson, T.; Poeckel, D.; Reader, V.; Strunk, K.; Sweetman, G.; Kruse, U.; Neubauer, G.; Ramsden, N. G.; Drewes, G. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes Nat. Biotechnol. 2011, 29, 255– 265
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    Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
    Bantscheff, Marcus; Hopf, Carsten; Savitski, Mikhail M.; Dittmann, Antje; Grandi, Paola; Michon, Anne-Marie; Schlegl, Judith; Abraham, Yann; Becher, Isabelle; Bergamini, Giovanna; Boesche, Markus; Delling, Manja; Duempelfeld, Birgit; Eberhard, Dirk; Huthmacher, Carola; Mathieson, Toby; Poeckel, Daniel; Reader, Valerie; Strunk, Katja; Sweetman, Gavain; Kruse, Ulrich; Neubauer, Gitte; Ramsden, Nigel G.; Drewes, Gerard
    Nature Biotechnology (2011), 29 (3), 255-265CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
    The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small mols. with megadalton protein complexes. A combination of affinity capture and quant. mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.
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  • Abstract

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    Figure 1

    Figure 1. [11C]6: a translational PET imaging probe. We have developed a potent HDAC imaging agent, termed [11C]6, incorporating three key structural features to create a versatile and translational probe for visualizing HDAC expression in vivo. Intravenous injection of trace amounts of [11C]6 (nanogram scale) in baboon and imaging by PET-MR demonstrates quantifiable uptake in the brain and in diverse peripheral organs. This illustrates the potential for [11C]6 as a broadly applicable tool in evaluating HDAC density in humans.

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    Scheme 1

    Scheme 1. Synthesis of 6, Its Radiolabeling Precursor (4) and [11C]6a
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    Scheme aReagents and conditions: (a) NaBH4, MeOH, overnight, rt, 75%; (b) formaldehyde, AcOH, NaBH4, MeOH, rt, overnight, 55%. (c) NH2OH (aq), 1M NaOH, MeOH/THF, 0 °C to rt, 4 h, 42% for 6, 40% for 5; RCY of [11C]6, 3–5% (non-decay corrected to trapped [11C]CH3I).

    Figure 2

    Figure 2. Kinetic modeling results with [11C]6 in baboon brain. (A) The total volume of distribution (VT) images from one representative animal show robust differences in radiotracer uptake at baseline and after blocking (0.5 mg/kg iv, 10 min pretreatment); (B) Two independent baseline-blocking studies were used to resolve quantitative VT data which show that pretreatment with unlabeled 6 (0.5 or 1.0 mg/kg) dose-dependently blocks tracer uptake in different baboon brain regions. WB: whole brain; CB: cerebellum; M1: primary motor cortex ; PU: putamen; TH: thalamus; V1: primary visual cortex ; CA: caudate; WM: white matter.

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    Figure 3

    Figure 3. [11C]6 PET-MR imaging. Axial views of summed PET images (40–80 min) superimposed with MR images from the same baboon following injection of radiotracer (4 mCi/baboon). Images illustrate tracer uptake in organs of interest at baseline and after pretreatment with unlabeled 6 (0.5 mg/kg). Robust blocking was observed in organs of interest including: A, heart; B, spleen; C, kidneys; and D, pancreas. Time–activity curves (baseline, blue; blocking, red) demonstrate a high specific binding of [11C]6 in these peripheral organs as the percent injected tracer dose per cm3 tissue is markedly reduced by blocking.

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  • References

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    This article references 45 other publications.

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      Nature (2012), 483 (7388), 222-6 ISSN:.
      Cognitive decline is a debilitating feature of most neurodegenerative diseases of the central nervous system, including Alzheimer's disease. The causes leading to such impairment are only poorly understood and effective treatments are slow to emerge. Here we show that cognitive capacities in the neurodegenerating brain are constrained by an epigenetic blockade of gene transcription that is potentially reversible. This blockade is mediated by histone deacetylase 2, which is increased by Alzheimer's-disease-related neurotoxic insults in vitro, in two mouse models of neurodegeneration and in patients with Alzheimer's disease. Histone deacetylase 2 associates with and reduces the histone acetylation of genes important for learning and memory, which show a concomitant decrease in expression. Importantly, reversing the build-up of histone deacetylase 2 by short-hairpin-RNA-mediated knockdown unlocks the repression of these genes, reinstates structural and synaptic plasticity, and abolishes neurodegeneration-associated memory impairments. These findings advocate for the development of selective inhibitors of histone deacetylase 2 and suggest that cognitive capacities following neurodegeneration are not entirely lost, but merely impaired by this epigenetic blockade.
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      A review. The expression of histone deacetylase 6 (HDAC6)-a versatile enzyme with a known role in epigenetics-increases significantly in the hippocampus and other relevant brain regions in both patients with Alzheimer's disease (AD) and animal models of AD. However, when and how HDAC6 expression increases during the course of AD progression remains unclear. Whether HDAC6 overexpression is an underlying cause of AD or a condition resulting from AD is controversial. Mounting evidence suggests that increased HDAC6 expression contributes to AD-assocd. neurodegeneration, although beneficial effects have also been identified. This review article addresses recent research on HDAC6 structure and function, and highlights the potential detrimental and protective roles of HDAC6 overexpression in AD. We hope to shed light on whether HDAC6 overexpression is assocd. with AD etiopathogenesis or whether it rescues AD-assocd. neurodegeneration compensatorily. Furthermore, we discuss new evidence showing that HDAC6 may be a therapeutic target for AD.
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      Biological Psychiatry (2013), 74 (9), 696-705CODEN: BIPCBF; ISSN:0006-3223. (Elsevier)
      Background: Postmortem brain studies have shown that HDAC1-a lysine deacetylase with broad activity against histones and nonhistone proteins-is frequently expressed at increased levels in prefrontal cortex (PFC) of subjects diagnosed with schizophrenia and related disease. However, it remains unclear whether upregulated expression of Hdac1 in the PFC could affect cognition and behavior. Methods: Using adeno-assocd. virus, an Hdac1 transgene was expressed in young adult mouse PFC, followed by behavioral assays for working and long-term memory, repetitive activity, and response to novelty. Prefrontal cortex transcriptomes were profiled by microarray. Antipsychotic drug effects were explored in mice treated for 21 days with haloperidol or clozapine. Results: Hdac1 overexpression in PFC neurons and astrocytes resulted in robust impairments in working memory, increased repetitive behaviors, and abnormal locomotor response profiles in novel environments. Long-term memory remained intact. Over 300 transcripts showed subtle but significant changes in Hdac1-overexpressing PFC. Major histocompatibility complex class II (MHC II)-related transcripts, including HLA-DQA1/H2-Aa, HLA-DQB1/H2-Ab1, and HLA-DRB1/H2-Eb1, located in the chromosome 6p21.3-22.1 schizophrenia and bipolar disorder risk locus, were among the subset of genes with a more robust (>1.5-fold) down-regulation in expression. Hdac1 levels declined during the course of normal PFC development. Antipsychotic drug treatment, including the atypical clozapine, did not affect Hdac1 levels in PFC but induced expression of multiple MHC II transcripts. Conclusions: Excessive HDAC1 activity, due to developmental defects or other factors, is assocd. with behavioral alterations and dysregulated expression of MHC II and other gene transcripts in the PFC.
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      Histone acetylation and deacetylation can be dynamically regulated in response to environmental stimuli and play important roles in learning and memory. Pharmacol. inhibition of histone deacetylases (HDACs) improves performance in learning tasks; however, many of these classical agents are "pan-HDAC" inhibitors, and their use makes it difficult to det. the roles of specific HDACs in cognitive function. We took a genetic approach using mice lacking the class I HDACs, HDAC1 or HDAC2, in postmitotic forebrain neurons to investigate the specificity or functional redundancy of these HDACs in learning and synaptic plasticity. We show that selective knock-out of Hdac2 led to a robust acceleration of the extinction rate of conditioned fear responses and a conditioned taste aversion as well as enhanced performance in an attentional set-shifting task. Hdac2 knock-out had no impact on episodic memory or motor learning, suggesting that the effects are task-dependent, with the predominant impact of HDAC2 inhibition being an enhancement in an animal's ability to rapidly adapt its behavioral strategy as a result of changes in associative contingencies. Our results demonstrate that the loss of HDAC2 improves associative learning, with no effect in nonassociative learning tasks, suggesting a specific role for HDAC2 in particular types of learning. HDAC2 may be an intriguing target for cognitive and psychiatric disorders that are characterized by an inability to inhibit behavioral responsiveness to maladaptive or no longer relevant assocns.
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      A review. Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The mol. mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several mol. mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the mol. mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments.
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      Journal of Neuroscience (2013), 33 (20), 8621-8632CODEN: JNRSDS; ISSN:0270-6474. (Society for Neuroscience)
      Histone deacetylase (HDAC) inhibitors have been used to promote neuronal survival and ameliorate neurol. dysfunction in a host of neurodegenerative disease models. The precise mol. mechanisms whereby HDAC inhibitors prevent neuronal death are currently the focus of intensive research. Here we demonstrate that HDAC inhibition prevents DNA damage-induced neurodegeneration by modifying the acetylation pattern of the tumor suppressor p53, which decreases its DNA-binding and transcriptional activation of target genes. Specifically, we identify that acetylation at K382 and K381 prevents p53 from assocg. with the pro-apoptotic PUMA gene promoter, activating transcription, and inducing apoptosis in mouse primary cortical neurons. Paradoxically, acetylation of p53 at the same lysines in various cancer cell lines leads to the induction of PUMA expression and death. Together, our data provide a mol. understanding of the specific outcomes of HDAC inhibition and suggest that strategies aimed at enhancing p53 acetylation at K381 and K382 might be therapeutically viable for capturing the beneficial effects in the CNS, without compromising tumor suppression.
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      The structure and function of chromatin can be altered by modifications to histone. Histone acetylation in vivo is a dynamic reversible process governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). HDAC6 is a unique isoform among the HDACs, and a gene expression pattern study, with cDNA microarray in MCF-7 cells, showed the HDAC6 gene to be late responsive, estrogen induced, and up-regulated. This led us to hypothesize that there was a link between levels of HDAC6 expression and the metastatic potential of breast cancer and also, therefore, the prognosis of these patients. In the present study, the level of HDAC6 mRNA expression was analyzed with quant. real-time reverse transcription-PCR, in 135 female patients with invasive breast cancer. HDAC6 protein expression was also detd. by immunohistochem. An assocn. was sought between HDAC6 expression and various clinicopathol. factors. HDAC6 mRNA was expressed at significantly higher levels in breast cancer patients with small tumors measuring less than 2 cm, with low histol. grade, and in estrogen receptor α- and progesterone receptor-pos. tumors. By contrast, no relationship was found between HDAC6 mRNA expression and any of the other clinicopathol. factors, namely, age, menopausal status, and axillary lymph node involvement. Patients expressing high levels of HDAC6 mRNA and protein had a better prognosis than those expressing low levels, in terms of disease-free survival. However, multivariate anal. failed to show that HDAC6 mRNA and protein are an independent prognostic factors for disease-free survival and overall survival. Furthermore, the patients with high levels of HDAC6 mRNA tended to be more responsive to endocrine treatment than those with low levels. Specific HDAC6 staining was found in the nucleus of some normal epithelial cells and in the cytoplasm of the majority of cancer cells. Although postmenopausal patients showed higher HDAC6 protein expression, there were no relationship between protein expression and any other clinicopathol. factors. We conclude that the levels of HDAC6 mRNA expression may have potential both as a marker of endocrine responsiveness and also as a prognostic indicator in breast cancer. Addnl. investigations are warranted concerning the relationship between HDAC6 expression and response to endocrine therapy.
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      The relationship between cisplatin resistance and histone deacetylase isoform overexpression in epithelial ovarian cancer cell lines
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      Journal of Gynecologic Oncology (2012), 23 (3), 182-189CODEN: JGOOAH; ISSN:2005-0380. (Korean Society of Gynecologic Oncology and Colposcopy)
      Objective: To investigate the relationship between cisplatin resistance and histone deacetylase (HDAC) isoform overexpression in ovarian cancer cell lines. Methods: Expression of four HDAC isoforms (HDAC 1, 2, 3, and 4) in two ovarian cancer cell lines, SKOV3 and OVCAR3, exposed to various concns. of cisplatin was examd. by western blot analyses. Cells were transfected with plasmid DNA of each HDAC. The overexpression of protein and mRNA of each HDAC was confirmed by western blot and reverse transcriptase-polymerase chain reaction analyses, resp. The cell viability of the SKOV3 and OVCAR3 cells transfected with HDAC plasmid DNA was measured using the cell counting kit-8 assay after treatment with cisplatin. Results: The 50% inhibitory concn. of the SKOV3 and OVCAR3 cells can be detd. 15-24 h after treatment with 15 μg/mL cisplatin. The expression level of acetylated histone 3 protein in SKOV3 cells increased after exposure to cisplatin. Compared with control cells at 24 h after cisplatin exposure, the viability of SKOV3 cells overexpressing HDAC 1 and 3 increased by 15% and 13% (p<0.05), resp. On the other hand, OVCAR3 cells that overexpressed HDAC 2 and 4 exhibited increased cell viability by 23% and 20% (p<0.05), resp., compared with control cells 24 h after exposure to cisplatin. Conclusion: In SKOV3 and OVCAR3 epithelial ovarian cancer cell lines, the correlation between HDAC overexpression and cisplatin resistance was confirmed. However, the specific HDAC isoform assocd. with resistance to cisplatin varied depending on the ovarian cancer cell line. These results may suggest that each HDAC isoform conveys cisplatin resistance via different mechanisms.
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    16. 16
      Hayashi, A.; Horiuchi, A.; Kikuchi, N.; Hayashi, T.; Fuseya, C.; Suzuki, A.; Konishi, I.; Shiozawa, T. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin Int. J. Cancer. 2010, 127, 1332– 1346
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      Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin
      Hayashi, Akiko; Horiuchi, Akiko; Kikuchi, Norihiko; Hayashi, Takuma; Fuseya, Chiho; Suzuki, Akihisa; Konishi, Ikuo; Shiozawa, Tanri
      International Journal of Cancer (2010), 127 (6), 1332-1346CODEN: IJCNAW; ISSN:0020-7136. (Wiley-Liss, Inc.)
      Histone acetylation/deacetylation controls chromatin activity and subsequent gene transcription. Recent studies demonstrated the activation of histone deacetylases (HDACs) in various human malignancies; however, the expression and function of HDACs in ovarian tumors are not fully understood. In this study, we examd. the immunohistochem. expression of HDAC1, HDAC2 and HDAC3 using tissues obtained from 115 cases of ovarian tumors and compared it with that of Ki-67 (a growth marker), p21, and E-cadherin and clinicopathol. parameters. In addn., we analyzed the effect of specific siRNA for HDAC1, HDAC2 and HDAC3 on the expression of cell cycle-related mols. and E-cadherin to clarify the functional difference among the 3 HDACs. The results indicated that the immunohistochem. expression of nuclear HDAC1, HDAC2 and HDAC3 proteins increased stepwise in benign, borderline and malignant tumors. The expression of HDAC1 and HDAC2 was correlated with Ki-67 expression and that of HDAC3 was inversely correlated with E-cadherin expression. Among the HDACs examd., only HDAC1 was assocd. with a poor outcome, when overexpressed. Treatment with HDAC inhibitors suppressed the proliferation of ovarian cancer cells in assocn. with apoptosis. A specific siRNA for HDAC1 significantly reduced the proliferation of ovarian carcinoma cells via downregulation of cyclin A expression, but siRNA for HDAC3 reduced the cell migration with elevated E-cadherin expression. Our results suggested that HDAC1 plays an important role in the proliferation of ovarian cancer cells, whereas HDAC3 functions in cell adhesion and migration. Therefore, specific therapeutic approaches should be considered according to the HDAC subtypes.
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    17. 17
      Benes, F. M.; Lim, B.; Matzilevich, D.; Walsh, J. P.; Subburaju, S.; Minns, M. Regulation of the GABA cell phenotype in hippocampus of schizophrenics and bipolars Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 10164– 10169
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    18. 18
      Broide, R. S.; Redwine, J. M.; Aftahi, N.; Young, W.; Bloom, F. E.; Winrow, C. J. Distribution of histone deacetylases 1–11 in the rat brain J. Mol. Neurosci. 2007, 31, 47– 58
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      Distribution of histone deacetylases 1-11 in the rat brain
      Broide, Ron S.; Redwine, Jeff M.; Aftahi, Najla; Young, Warren; Bloom, Floyd E.; Winrow, Christopher J.
      Journal of Molecular Neuroscience (2007), 31 (1), 47-58CODEN: JMNEES; ISSN:0895-8696. (Humana Press Inc.)
      Although protein phosphorylation has been characterized more extensively, modulation of the acetylation state of signaling mols. is now being recognized as a key means of signal transduction. The enzymes responsible for mediating these changes include histone acetyltransferases and histone deacetylases (HDACs). Members of the HDAC family of enzymes have been identified as potential therapeutic targets for diseases ranging from cancer to ischemia and neurodegeneration. The authors initiated a project to conduct comprehensive gene expression mapping of the 11 HDAC isoforms (HDAC1-11) (classes I, II, and IV) throughout the rat brain using high-resoln. in situ hybridization (ISH) and imaging technol. Internal and external data bases were employed to identify the appropriate rat sequence information for probe selection. In addn., immunohistochem. was performed on these samples to sep. examine HDAC expression in neurons, astrocytes, oligodendrocytes, and endothelial cells in the CNS. This double-labeling approach enabled the identification of specific cell types in which the individual HDACs were expressed. The signals obtained by ISH were compared to radiolabeled stds. and thereby enabled semiquant. anal. of individual HDAC isoforms and defined relative levels of gene expression in >50 brain regions. This project produced an extensive atlas of 11 HDAC isoforms throughout the rat brain, including cell type localization, providing a valuable resource for examg. the roles of specific HDACs in the brain and the development of future modulators of HDAC activity.
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    19. 19
      Hooker, J. M.; Kim, S. W.; Alexoff, D.; Xu, Y.; Shea, C.; Reid, A.; Volkow, N.; Fowler, J. S. Histone deacetylase inhibitor, MS-275, exhibits poor brain penetration: PK studies of [11C]MS-275 using Positron Emission Tomography ACS Chem. Neurosci. 2010, 1, 65– 73
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      19
      Histone Deacetylase Inhibitor MS-275 Exhibits Poor Brain Penetration: Pharmacokinetic Studies of [11C]MS-275 using Positron Emission Tomography
      Hooker, Jacob M.; Kim, Sung Won; Alexoff, David; Xu, Youwen; Shea, Colleen; Reid, Alicia; Volkow, Nora; Fowler, Joanna S.
      ACS Chemical Neuroscience (2010), 1 (1), 65-73CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      MS-275 (entinostat) is a histone deacetylase (HDAC) inhibitor currently in clin. trials for the treatment of several types of cancer. Recent reports have noted that MS-275 can cross the blood-brain barrier (BBB) and cause region-specific changes in rodent brain histone acetylation. To characterize the pharmacokinetics and distribution of MS-275 in the brain using positron emission tomog. (PET), we labeled the carbamate carbon of MS-275 with carbon-11. Using PET, we detd. that [11C]MS-275 has low uptake in brain tissue when administered i.v. to nonhuman primates. In rodent studies, we obsd. that pharmacokinetics and brain accumulation of [11C]MS-275 were not changed by the coadministration of large doses of unlabeled MS-275. These results, which both highlight the poor brain penetration of MS-275, clearly suggest its limitation as a therapeutic agent for the central nervous system (CNS). Moreover, our study demonstrates the effectiveness of PET at providing brain pharmacokinetic data for HDAC inhibitors. These data are important not only for the development of new compds. for peripheral cancer treatment (where CNS exclusion is often advantageous) but also for the treatment of neurol. disorders (where CNS penetration is crit.).
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    20. 20
      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.; Nishi, R.; Mizuma, H.; Onoe, H.; Kagawa, S.; Higashi, T.; Fukumitsu, N.; Alauddin, M.; Tong, W.; Herholz, K.; Gelovani, J. G. Imaging epigenetic regulation by histone deacetylases in the brain using PET/MRI with (1)(8)F-FAHA Neuroimage 2013, 64, 630– 639
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      Hendricks, J. A.; Keliher, E. J.; Marinelli, B.; Reiner, T.; Weissleder, R.; Mazitschek, R. In vivo PET imaging of histone deacetylases by 18F-suberoylanilide hydroxamic acid (18F-SAHA) J. Med. Chem. 2011, 54, 5576– 5582
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      Seo, Y. J.; Kang, Y.; Muench, L.; Reid, A.; Caesar, S.; Jean, L.; Fevier-Wagner, F.; Holson, E. B.; Haggarty, S. J.; Weiss, P.; King, P.; Carter, P.; Volkow, N. D.; Fowler, J. S.; Hooker, J. M.; Kim, S. W. Image-guided synthesis reveals potent blood-brain barrier permeable histone deacetylase inhibitors ACS Chem. Neurosci. 2014, 5, 588– 596
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      22
      Image-Guided Synthesis Reveals Potent Blood-Brain Barrier Permeable Histone Deacetylase Inhibitors
      Seo, Young Jun; Kang, Yeona; Muench, Lisa; Reid, Alicia; Caesar, Shannon; Jean, Logan; Wagner, Florence; Holson, Edward; Haggarty, Stephen J.; Weiss, Philipp; King, Payton; Carter, Pauline; Volkow, Nora D.; Fowler, Joanna S.; Hooker, Jacob M.; Kim, Sung Won
      ACS Chemical Neuroscience (2014), 5 (7), 588-596CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Recent studies have revealed that several histone deacetylase (HDAC) inhibitors, which are used to study/treat brain diseases, show low blood-brain barrier (BBB) penetration. In addn. to low HDAC potency and selectivity obsd., poor brain penetrance may account for the high doses needed to achieve therapeutic efficacy. Here the authors report the development and evaluation of highly potent and blood-brain barrier permeable HDAC inhibitors for CNS applications based on an image-guided approach involving the parallel synthesis and radiolabeling of a series of compds. based on the benzamide HDAC inhibitor, MS-275 as a template. BBB penetration was optimized by rapid carbon-11 labeling and PET imaging in the baboon model and using the imaging derived data on BBB penetration from each compd. to feed back into the design process. A total of 17 compds. were evaluated, revealing mols. with both high binding affinity and BBB permeability. A key element conferring BBB penetration in this benzamide series was a basic benzylic amine. These derivs. exhibited 1-100 nM inhibitory activity against recombinant human HDAC1 and HDAC2. Three of the carbon-11 labeled aminomethyl benzamide derivs. showed high BBB penetration (∼0.015%ID/cc) and regional binding heterogeneity in the brain (high in thalamus and cerebellum). Taken together this approach has afforded a strategy and a predictive model for developing highly potent and BBB permeable HDAC inhibitors for CNS applications and for the discovery of novel candidate mols. for small mol. probes and drugs.
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    23. 23
      Seo, Y. J.; Muench, L.; Reid, A.; Chen, J.; Kang, Y.; Hooker, J. M.; Volkow, N. D.; Fowler, J. S.; Kim, S. W. Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain Bioorg. Med. Chem. Lett. 2013, 23, 6700– 6705
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      Hanson, J. E.; La, H.; Plise, E.; Chen, Y. H.; Ding, X.; Hanania, T.; Sabath, E. V.; Alexandrov, V.; Brunner, D.; Leahy, E.; Steiner, P.; Liu, L.; Scearce-Levie, K.; Zhou, Q. SAHA enhances synaptic function and plasticity in vitro but has limited brain availability in vivo and does not impact cognition PLoS One 2013, 8, e69964
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      Maugh, T. H., 2nd Panel urges wide use of antiviral drug Science 1979, 206, 1058– 1060
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      Banister, S. D.; Wilkinson, S. M.; Longworth, M.; Stuart, J.; Apetz, N.; English, K.; Brooker, L.; Goebel, C.; Hibbs, D. E.; Glass, M.; Connor, M.; McGregor, I. S.; Kassiou, M. The synthesis and pharmacological evaluation of adamantane-derived indoles: cannabimimetic drugs of abuse ACS Chem. Neurosci. 2013, 4, 1081– 1092
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      The Synthesis and Pharmacological Evaluation of Adamantane-Derived Indoles: Cannabimimetic Drugs of Abuse
      Banister, Samuel D.; Wilkinson, Shane M.; Longworth, Mitchell; Stuart, Jordyn; Apetz, Nadine; English, Katrina; Brooker, Lance; Goebel, Catrin; Hibbs, David E.; Glass, Michelle; Connor, Mark; McGregor, Iain S.; Kassiou, Michael
      ACS Chemical Neuroscience (2013), 4 (7), 1081-1092CODEN: ACNCDM; ISSN:1948-7193. (American Chemical Society)
      Two novel adamantane derivs., adamantan-1-yl(1-pentyl-1H-indol-3-yl)methanone (AB-001) and N-(adamtan-1-yl)-1-pentyl-1H-indole-3-carboxamide (SDB-001), were recently identified as cannabimimetic indoles of abuse. Conflicting anecdotal reports of the psychoactivity of AB-001 in humans, and a complete dearth of information about the bioactivity of SDB-001, prompted the prepn. of AB-001, SDB-001, and several analogs intended to explore preliminary structure-activity relationships within this class. This study sought to elucidate which structural features of AB-001, SDB-001, and their analogs govern the cannabimimetic potency of these chemotypes in vitro and in vivo. All compds. showed similar full agonist profiles at CB1 (EC50 = 16-43 nM) and CB2 (EC50 = 29-216 nM) receptors in vitro using a FLIPR membrane potential assay, with the exception of SDB-002, which demonstrated partial agonist activity at CB2 receptors. The activity of AB-001, AB-002, and SDB-001 in rats was compared to that of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabimimetic indole JWH-018 using biotelemetry. SDB-001 dose-dependently induced hypothermia and reduced heart rate (maximal dose 10 mg/kg) with potency comparable to that of Δ9-tetrahydrocannabinol (Δ9-THC, maximal dose 10 mg/kg), and lower than that of JWH-018 (maximal dose 3 mg/kg). Addnl., the changes in body temp. and heart rate affected by SDB-001 are of longer duration than those of Δ9-THC or JWH-018, suggesting a different pharmacokinetic profile. In contrast, AB-001, and its homolog, AB-002, did not produce significant hypothermic and bradycardic effects, even at relatively higher doses (up to 30 mg/kg), indicating greatly reduced potency compared to Δ9-THC, JWH-018, and SDB-001.
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    27. 27
      Gopalan, B.; Ponpandian, T.; Kachhadia, V.; Bharathimohan, K.; Vignesh, R.; Sivasudar, V.; Narayanan, S.; Mandar, B.; Praveen, R.; Saranya, N.; Rajagopal, S. Discovery of adamantane based highly potent HDAC inhibitors Bioorg. Med. Chem. Lett. 2013, 23, 2532– 2537
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      Farde, L.; Eriksson, L.; Blomquist, G.; Halldin, C. Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET--a comparison to the equilibrium analysis J. Cereb. Blood Flow Metab. 1989, 9, 696– 708
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      Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET - a comparison to the equilibrium analysis
      Farde, L.; Eriksson, L.; Blomquist, G.; Halldin, C.
      Journal of Cerebral Blood Flow and Metabolism (1989), 9 (5), 696-708CODEN: JCBMDN; ISSN:0271-678X.
      [11C]raclopride binding to central D2-dopamine receptors in humans has previously been examd. by positron emission tomog. (PET). Based on the rapid occurrence of binding equil., a satn. anal. was developed for the detn. of receptor d. (Bmax) and affinity (Kd). For anal. of PET measurements obtained with other ligands, a kinetic 3-compartment model was used. In the present study, the brain uptake of [11C]raclopride was analyzed further by applying both a kinetic and an equil. anal. to data obtained from 4 PET expts. in each of 3 healthy subjects. First regional cerebral blood vol. was detd. In the second and third expt., [11C]raclopride with high and low specific activity was used. In a fourth expt., the [11C]raclopride enantiomer [11C]FLB472 was used to examine the concn. of free radioligand and nonspecific binding in brain. Radioactivity in arterial blood was measured using an automated blood sampling system. Bmax And Kd values for [11C]raclopride binding could be detd. also with the kinetic anal. As expected theor., those values were similar to those obtained with the equil. anal. In addn., the kinetic anal. allowed sep. detn. of the assocn. and dissocn. rate consts., kon and koff, resp. Examn. of [11C]raclopride and [11C]FLB472 uptake in brain regions devoid of specific D2-dopamine receptor binding indicated a fourth compartment in which uptake was reversible, nonstereoselective, and nonsaturable in the dose range studied.
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    29. 29
      Innis, R. B.; Cunningham, V. J.; Delforge, J.; Fujita, M.; Gjedde, A.; Gunn, R. N.; Holden, J.; Houle, S.; Huang, S. C.; Ichise, M.; Iida, H.; Ito, H.; Kimura, Y.; Koeppe, R. A.; Knudsen, G. M.; Knuuti, J.; Lammertsma, A. A.; Laruelle, M.; Logan, J.; Maguire, R. P.; Mintun, M. A.; Morris, E. D.; Parsey, R.; Price, J. C.; Slifstein, M.; Sossi, V.; Suhara, T.; Votaw, J. R.; Wong, D. F.; Carson, R. E. Consensus nomenclature for in vivo imaging of reversibly binding radioligands J. Cereb. Blood Flow Metab. 2007, 27, 1533– 1539
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      Consensus nomenclature for in vivo imaging of reversibly binding radioligands
      Innis, Robert B.; Cunningham, Vincent J.; Delforge, Jacques; Fujita, Masahiro; Gjedde, Albert; Gunn, Roger N.; Holden, James; Houle, Sylvain; Huang, Sung-Cheng; Ichise, Masanori; Iida, Hidehiro; Ito, Hiroshi; Kimura, Yuichi; Koeppe, Robert A.; Knudsen, Gitte M.; Knuuti, Juhani; Lammertsma, Adriaan A.; Laruelle, Marc; Logan, Jean; Maguire, Ralph Paul; Mintun, Mark A.; Morris, Evan D.; Parsey, Ramin; Price, Julie C.; Slifstein, Mark; Sossi, Vesna; Suhara, Tetsuya; Votaw, John R.; Wong, Dean F.; Carson, Richard E.
      Journal of Cerebral Blood Flow & Metabolism (2007), 27 (9), 1533-1539CODEN: JCBMDN; ISSN:0271-678X. (Nature Publishing Group)
      A review. An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo mol. imaging of reversibly binding radioligands.
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    30. 30
      Wang, Y.; Zhang, Y. L.; Hennig, K.; Gale, J. P.; Hong, Y.; Cha, A.; Riley, M.; Wagner, F.; Haggarty, S. J.; Holson, E.; Hooker, J. Class I HDAC imaging using [ (3)H]CI-994 autoradiography Epigenetics 2013, 8, 756– 764
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      Schroeder, F. A.; Lewis, M. C.; Fass, D. M.; Wagner, F. F.; Zhang, Y. L.; Hennig, K. M.; Gale, J.; Zhao, W. N.; Reis, S.; Barker, D. D.; Berry-Scott, E.; Kim, S. W.; Clore, E. L.; Hooker, J. M.; Holson, E. B.; Haggarty, S. J.; Petryshen, T. L. A selective HDAC 1/2 inhibitor modulates chromatin and gene expression in brain and alters mouse behavior in two mood-related tests PLoS One 2013, 8, e71323
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      Fass, D. M.; Schroeder, F. A.; Perlis, R. H.; Haggarty, S. J. Epigenetic mechanisms in mood disorders: Targeting neuroplasticity Neuroscience 2014, 264, 112– 130
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      Davies, G.; Tenesa, A.; Payton, A.; Yang, J.; Harris, S. E.; Liewald, D.; Ke, X.; Le Hellard, S.; Christoforou, A.; Luciano, M.; McGhee, K.; Lopez, L.; Gow, A. J.; Corley, J.; Redmond, P.; Fox, H. C.; Haggarty, P.; Whalley, L. J.; McNeill, G.; Goddard, M. E.; Espeseth, T.; Lundervold, A. J.; Reinvang, I.; Pickles, A.; Steen, V. M.; Ollier, W.; Porteous, D. J.; Horan, M.; Starr, J. M.; Pendleton, N.; Visscher, P. M.; Deary, I. J. Genome-wide association studies establish that human intelligence is highly heritable and polygenic Mol. Psychiatry 2011, 16, 996– 1005
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      Genome-wide association studies establish that human intelligence is highly heritable and polygenic
      Davies, G.; Tenesa, A.; Payton, A.; Yang, J.; Harris, S. E.; Liewald, D.; Ke, X.; Le Hellard, S.; Christoforou, A.; Luciano, M.; McGhee, K.; Lopez, L.; Gow, A. J.; Corley, J.; Redmond, P.; Fox, H. C.; Haggarty, P.; Whalley, L. J.; McNeill, G.; Goddard, M. E.; Espeseth, T.; Lundervold, A. J.; Reinvang, I.; Pickles, A.; Steen, V. M.; Ollier, W.; Porteous, D. J.; Horan, M.; Starr, J. M.; Pendleton, N.; Visscher, P. M.; Deary, I. J.
      Molecular Psychiatry (2011), 16 (10), 996-1005CODEN: MOPSFQ; ISSN:1359-4184. (Nature Publishing Group)
      General intelligence is an important human quant. trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly assocd. with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. The authors conducted a genome-wide anal. of 3511 unrelated adults with data on 549 692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. They est. that 40% of the variation in crystd.-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequil. between genotyped common SNP markers and unknown causal variants. These ests. provide lower bounds for the narrow-sense heritability of the traits. The authors partitioned genetic variation on individual chromosomes and found that, on av., longer chromosomes explain more variation. Finally, using just SNP data the authors predicted ∼1% of the variance of crystd. and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, resp.). These results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence. Mol. Psychiatry (2011) 16, 996-1005; doi:10.1038/mp.2011.85; published online 9 August 2011.
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      McPherson, R. From genome-wide association studies to functional genomics: new insights into cardiovascular disease Can. J. Cardiol. 2013, 29, 23– 29
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      From genome-wide association studies to functional genomics: new insights into cardiovascular disease
      McPherson Ruth
      The Canadian journal of cardiology (2013), 29 (1), 23-9 ISSN:.
      Genome-wide association studies (GWASs) for coronary artery disease (CAD) have identified more than 30 variants robustly associated with CAD risk. The majority are not associated with conventional risk factors but highlight novel pathways, including cellular proliferation. Although some risk variants are nonsynonymous coding variants resulting in an amino acid change in the encoded protein, the majority are in noncoding regions of the genome and may encompass multiple signals of variable effect. The use of genetic data for development of new therapies requires the identification of causative genetic variants and elucidation of the molecular mechanisms by which they predispose to CAD. The computational and laboratory approaches for the interpretation of GWAS data are discussed with a particular focus on noncoding variants, including the study of regulatory elements, the evaluation of nonsynonymous coding variants, and expression quantitative trait locus analysis for the integration of GWAS data with genome-wide messenger RNA expression data.
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    35. 35
      Torres, J. M.; Cox, N. J.; Philipson, L. H. Genome wide association studies for diabetes: perspective on results and challenges Pediatr. Diabetes 2013, 14, 90– 96
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      Genome wide association studies for diabetes: perspective on results and challenges
      Torres, J. M.; Cox, N. J.; Philipson, L. H.
      Pediatric Diabetes (2013), 14 (2), 90-96CODEN: PDEIBT; ISSN:1399-5448. (Wiley-Blackwell)
      A review. Recent results of genome wide assocn. study (GWAS) for diabetes genes, while reaching impressive tech. milestones and implicating new findings for research, have been uniformly disappointing in terms of immediate clin. utility. The relative risk assocd. with any of the newly reported genetic loci, or even considering all of them together, is far less than simply that which can be obtained by taking a history and a phys. exam. For type 2 diabetes (T2D), GWAS have implicated novel pathways, supported previously known assocns., and highlighted the importance of the beta cell and insulin secretion. Monogenic forms of diabetes, on the other hand, continue to yield interesting insights into genes controlling human beta cell function but most cases of monogenic diabetes are simply not diagnosed. Here, we briefly review recent results related to type 1, type 2 and maturity onset diabetes of youth (MODY) diabetes and suggest that future studies emphasizing quant. traits are likely to yield even more insights.
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    36. 36
      Mells, G. F.; Kaser, A.; Karlsen, T. H. Novel insights into autoimmune liver diseases provided by genome-wide association studies J. Autoimmun. 2013, 46, 41– 54
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      Novel insights into autoimmune liver diseases provided by genome-wide association studies
      Mells, George F.; Kaser, Arthur; Karlsen, Tom H.
      Journal of Autoimmunity (2013), 46 (), 41-54CODEN: JOAUEP; ISSN:0896-8411. (Elsevier Ltd.)
      A review. Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify mol. targets for pharmacotherapy. Early genetic studies consisted of HLA assocn. studies and non-HLA candidate gene assocn. studies, designed to identify assocn. with selected HLA or non-HLA loci. HLA assocn. studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak assocns. detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide assocn. studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clin. conditions. The specific genetic basis of these PBC and PSC assocd. inflammatory themes as detd. by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.
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      Bowcock, A. M. Genome-wide association studies and infectious disease Crit. Rev. Immunol. 2010, 30, 305– 309
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      Genome-wide association studies and infectious disease
      Bowcock, Anne M.
      Critical Reviews in Immunology (2010), 30 (3), 305-309CODEN: CCRIDE; ISSN:1040-8401. (Begell House, Inc.)
      A review. The identification of genetic variants predisposing to complex diseases and phenotypes represent a challenge for geneticists in the early part of the 21st century. These are not simple Mendelian disorders caused by single mutations, such as cystic fibrosis or Huntington's disease, but common diseases that are usually polygenic in origin. The predisposing genes can be susceptibility factors or protective factors. One example of such a complex disease is the inflammatory skin disease psoriasis. However, another example could be protection from an infectious disease. Both of these phenotypes are due in part to the presence of low-risk variants in the host. Moreover, all of these complex phenotypes require environmental triggers as well and, in the case of infectious diseases, these are pathogens. In the case of other common diseases such as cardiovascular disease the triggers are often lifestyle-related issues such as diet or exercise. Genome-wide assocn. studies are now identifying some of these genetic susceptibility factors.
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    38. 38
      Xu, C.; Aragam, N.; Li, X.; Villla, E. C.; Wang, L.; Briones, D.; Petty, L.; Posada, Y.; Arana, T. B.; Cruz, G.; Mao, C.; Camarillo, C.; Su, B. B.; Escamilla, M. A.; BCL9, Wang K. and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies PLoS One 2013, 8, e51674
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      Wang, C.; Schroeder, F. A.; Hooker, J. M. Visualizing epigenetics: Current advances and advantages in HDAC PET imaging techniques Neuroscience 2014, 264, 186– 197
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      Tang, J.; Yan, Y.; Zhao, T. C.; Gong, R.; Bayliss, G.; Yan, H.; Zhuang, S.; Class, I. HDAC activity is required for renal protection and regeneration after acute kidney injury Am. J. Physiol. Renal Physiol. 2014, 307, F303– 16
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      Schroeder, F. A.; Lin, C. L.; Crusio, W. E.; Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse Biol. Psychiatry 2007, 62, 55– 64
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      Antidepressant-Like Effects of the Histone Deacetylase Inhibitor, Sodium Butyrate, in the Mouse
      Schroeder, Frederick A.; Lin, Cong Lily; Crusio, Wim E.; Akbarian, Schahram
      Biological Psychiatry (2007), 62 (1), 55-64CODEN: BIPCBF; ISSN:0006-3223. (Elsevier Inc.)
      Chromatin remodeling, including changes in histone acetylation, might play a role in the pathophysiol. and treatment of depression. We investigated whether the histone deacetylase inhibitor sodium butyrate (SB) administered as single drug or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine exerts antidepressant-like effects in mice. Mice (C57BL/6J) received injections of SB, fluoxetine, or a combination of both drugs either acutely or chronically for a period of 28 days and were subjected to a battery of tests to measure anxiety and behavioral despair. Histone acetylation and expression of brain-derived neurotrophic factor (BDNF) were monitored in hippocampus and frontal cortex. Co-treatment with SB and fluoxetine resulted in a significant 20-40% decrease in immobility scores in the tail suspension test (TST), a measure for behavioral despair, both acutely and chronically. In contrast, decreased immobility after single drug regimens was limited either to the acute (fluoxetine) or chronic (SB) paradigm. Systemic injection of SB induced short-lasting histone hyperacetylation in hippocampus and frontal cortex. Among the four treatment paradigms that resulted in improved immobility scores in the TST, three were assocd. with a transient, at least 50% increase in BDNF transcript in frontal cortex, whereas changes in hippocampus were less consistent. The histone deacetylase inhibitor SB exerts antidepressant-like effects in the mouse. The therapeutic benefits and mol. actions of histone modifying drugs, including co-treatment with SSRIs and other newer generation antidepressant medications, warrant further exploration in exptl. models.
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    42. 42
      Reid, A. E.; Hooker, J.; Shumay, E.; Logan, J.; Shea, C.; Kim, S. W.; Collins, S.; Xu, Y.; Volkow, N.; Fowler, J. S. Evaluation of 6-([(18)F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain Nucl. Med. Biol. 2009, 36, 247– 258
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      42
      Evaluation of 6-([18F]fluoroacetamido)-1-hexanoicanilide for PET imaging of histone deacetylase in the baboon brain
      Reid, Alicia E.; Hooker, Jacob; Shumay, Elena; Logan, Jean; Shea, Colleen; Kim, Sung Won; Collins, Shanika; Xu, Youwen; Volkow, Nora; Fowler, Joanna S.
      Nuclear Medicine and Biology (2009), 36 (3), 247-258CODEN: NMBIEO; ISSN:0969-8051. (Elsevier Inc.)
      Introduction: Histone deacetylases (HDACs) are enzymes involved in epigenetic modifications that shift the balance toward chromatin condensation and silencing of gene expression. Here, we evaluate the utility of 6-([18F]fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) for positron emission tomog. imaging of HDAC activity in the baboon brain. For this purpose, we assessed its in vivo biodistribution, sensitivity to HDAC inhibition, metabolic stability and the distribution of the putative metabolite [18F]fluoroacetate ([18F]FAC). Methods: [18F]FAHA and its metabolite [18F]FAC were prepd., and their in vivo biodistribution and pharmacokinetics were detd. in baboons. [18F]FAHA metab. and its sensitivity to HDAC inhibition using suberanilohydroxamic acid (SAHA) were assessed in arterial plasma and by in vitro incubation studies. The chem. form of F-18 in rodent brain was assessed by ex vivo studies. Distribution vols. for [18F]FAHA in the brain were derived. Results: [18F]FAHA was rapidly metabolized to [18F]FAC, and both labeled compds. entered the brain. [18F]FAHA exhibited regional differences in brain uptake and kinetics. In contrast, [18F]FAC showed little variation in regional brain uptake and kinetics. A kinetic anal. that takes into account the uptake of peripherally produced [18F]FAC indicated that SAHA inhibited binding of [18F]FAHA in the baboon brain dose-dependently. In vitro studies demonstrated SAHA-sensitive metab. of [18F]FAHA to [18F]FAC within the cell and diffusion of [18F]FAC out of the cell. All radioactivity in brain homogenate from rodents was [18F]FAC at 7 min postinjection of [18F]FAHA. Conclusion: The rapid metab. of [18F]FAHA to [18F]FAC in the periphery complicates the quant. anal. of HDAC in the brain. However, dose-dependent blocking studies with SAHA and kinetic modeling indicated that a specific interaction of [18F]FAHA in the brain was obsd. Validating the nature of this interaction as HDAC specific will require addnl. studies.
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      Black, K. J.; Koller, J. M.; Snyder, A. Z.; Perlmutter, J. S. Atlas template images for nonhuman primate neuroimaging: baboon and macaque Methods Enzymol. 2004, 385, 91– 102
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      Logan, J.; Fowler, J. S.; Volkow, N. D.; Wang, G. J.; Ding, Y. S.; Alexoff, D. L. Distribution volume ratios without blood sampling from graphical analysis of PET data J. Cereb. Blood Flow Metab. 1996, 16, 834– 840
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      44
      Distribution volume ratios without blood sampling from graphical analysis of PET data
      Logan J; Fowler J S; Volkow N D; Wang G J; Ding Y S; Alexoff D L
      Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism (1996), 16 (5), 834-40 ISSN:0271-678X.
      The distribution volume ratio (DVR), which is a linear function of receptor availability, is widely used as a model parameter in imaging studies. The DVR corresponds to the ratio of the DV of a receptor-containing region to a nonreceptor region and generally requires the measurement of an arterial input function. Here we propose a graphical method for determining the DVR that does not require blood sampling. This method uses data from a nonreceptor region with an average tissue-to-plasma efflux constant k2 to approximate the plasma integral. Data from positron emission tomography studies with [11C]raclopride (n = 20) and [11C]d-threo-methylphenidate ([11C]dMP) (n = 8) in which plasma data were taken and used to compare results from two graphical methods, one that uses plasma data and one that does not. k2 was 0.163 and 0.051 min-1 for [11C]raclopride and [11C]dMP, respectively. Results from both methods were very similar, and the average percentage difference between the methods was -0.11% for [11C]raclopride and 0.46% for [11C]dMP for DVR of basal ganglia (BG) to cerebellum (CB). Good agreement between the two methods was also achieved for DVR images created by both methods. This technique provides an alternative method of analysis not requiring blood sampling that gives equivalent results for the two ligands studied. It requires initial studies with blood sampling to determine the average kinetic constant and to test applicability. In some cases, it may be possible to neglect the k2 term if the BG/CB ratio becomes reasonably constant for a sufficiently long period of time over the course of the experiment.
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    45. 45
      Bantscheff, M.; Hopf, C.; Savitski, M. M.; Dittmann, A.; Grandi, P.; Michon, A. M.; Schlegl, J.; Abraham, Y.; Becher, I.; Bergamini, G.; Boesche, M.; Delling, M.; Dumpelfeld, B.; Eberhard, D.; Huthmacher, C.; Mathieson, T.; Poeckel, D.; Reader, V.; Strunk, K.; Sweetman, G.; Kruse, U.; Neubauer, G.; Ramsden, N. G.; Drewes, G. Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes Nat. Biotechnol. 2011, 29, 255– 265
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      45
      Chemoproteomics profiling of HDAC inhibitors reveals selective targeting of HDAC complexes
      Bantscheff, Marcus; Hopf, Carsten; Savitski, Mikhail M.; Dittmann, Antje; Grandi, Paola; Michon, Anne-Marie; Schlegl, Judith; Abraham, Yann; Becher, Isabelle; Bergamini, Giovanna; Boesche, Markus; Delling, Manja; Duempelfeld, Birgit; Eberhard, Dirk; Huthmacher, Carola; Mathieson, Toby; Poeckel, Daniel; Reader, Valerie; Strunk, Katja; Sweetman, Gavain; Kruse, Ulrich; Neubauer, Gitte; Ramsden, Nigel G.; Drewes, Gerard
      Nature Biotechnology (2011), 29 (3), 255-265CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
      The development of selective histone deacetylase (HDAC) inhibitors with anti-cancer and anti-inflammatory properties remains challenging in large part owing to the difficulty of probing the interaction of small mols. with megadalton protein complexes. A combination of affinity capture and quant. mass spectrometry revealed the selectivity with which 16 HDAC inhibitors target multiple HDAC complexes scaffolded by ELM-SANT domain subunits, including a novel mitotic deacetylase complex (MiDAC). Inhibitors clustered according to their target profiles with stronger binding of aminobenzamides to the HDAC NCoR complex than to the HDAC Sin3 complex. We identified several non-HDAC targets for hydroxamate inhibitors. HDAC inhibitors with distinct profiles have correspondingly different effects on downstream targets. We also identified the anti-inflammatory drug bufexamac as a class IIb (HDAC6, HDAC10) HDAC inhibitor. Our approach enables the discovery of novel targets and inhibitors and suggests that the selectivity of HDAC inhibitors should be evaluated in the context of HDAC complexes and not purified catalytic subunits.
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    The results of off-target binding, mPET imaging in rodents and SAHA pretreated study in NHP were shown in Table S1, Figure S1–S6. This material is available free of charge via the Internet at http://pubs.acs.org.


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