The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

Zeglis, Brian M.; Pillarsetty, Nagavarakishore; Divilov, Vadim; Blasberg, Ronald; Lewis, Jason S.

doi:10.1016/j.nucmedbio.2010.12.008

Cited by 17 publications

(17 citation statements)

References 52 publications

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“…Other investigators have explored the feasibility of PET imaging of HDACs expression using radiolabeled HDAC inhibitors, such as [ 18 F]suberoylanilide hydroxamic acid, [ 18 F]SAHA (Hendricks, et al 2011; Zeglis, et al 2011) and [ 11 C]MS-275 (Hooker, et al 2010). However, both [ 18 F]SAHA and [ 11 C]MS-275 did not accumulate in the brain due to either excessive washout, such as in case of [ 18 F]SAHA, or poor blood-brain barrier (BBB) permeability, such as in case of [ 11 C]MS-275.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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Epigenetic modifications mediated by histone deacetylases (HDACs) play important roles in the mechanisms of different neurologic diseases and HDAC inhibitors (HDACIs) have shown promise in therapy. However, pharmacodynamic profiles of many HDACIs in the brain remain largely unknown due to the lack of validated methods for noninvasive imaging of HDACs expression-activity. In this study, dynamic PET/CT imaging was performed in 4 rhesus macaques using [18F]FAHA, a novel HDAC substrate, and [18F]fluoroacetate, the major radio-metabolite of [18F]FAHA, and fused with corresponding MR images of the brain. Quantification of [18F]FAHA accumulation in the brain was performed using a customized dual-tracer pharmacokinetic model. Immunohistochemical analyses of brain tissue revealed the heterogeneity of expression of individual HDACs in different brain structures and cell types and confirmed that PET/CT/MRI with [18F]FAHA reflects the level of expression-activity of HDAC class IIa enzymes. Furthermore, PET/CT/MRI with [18F]FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of HDACs inhibitor SAHA in the brain.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2013

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“…15 [ 18 F]FAHA is a HDAC substrate rather than an inhibitor and manifests very rapid metabolism to [ 18 F]fluoroacetate which can be trapped in the brain. 14 More recently, hyroxamate inhibitors, F-18 labelled SAHA derivatives ([ 18 F]SAHA 16 , [ 18 F]FESAHA 17 ) were synthesized and evaluated in a mouse tumor model. While [ 18 F]SAHA 16 showed HDAC specific binding in tumor, both of them showed very poor BBB permeability.…”

mentioning

confidence: 99%

“…Based on the [ 18 F]FESAHA 17 and [ 18 F]FAHA PET studies, we set out to develop a high affinity radiotracer which also crosses the BBB freely and is metabolically stable for PET studies of brain HDAC in humans. Our preference has been to radiolabel with carbon-11 since its short half-life (20.4 min) enables the performance of serial studies in the same day wherein a subject or patients can serve as his/her own control.…”

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confidence: 99%

Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain

Seo

Muench

Reid

et al. 2013

Bioorganic & Medicinal Chemistry Letters

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Histone deacetylases (HDACs) regulate gene expression by inducing conformational changes in chromatin. Ever since the discovery of a naturally occurring HDAC inhibitor, trichostatin A (TSA) stimulated the recent development of suberoylanilide (SAHA, Zolinza®), HDAC has become an important molecular target for drug development. This has created the need to develop specific in vivo radioligands to study epigenetic regulation and HDAC engagement for drug development for diseases including cancer and psychiatric disorders. 6-([18F]Fluoroacetamido)-1-hexanoicanilide ([18F]FAHA) was recently developed as a HDAC substrate and shows moderate blood-brain barrier (BBB) permeability and specific signal (by metabolic trapping/or deacetylation) but rapid metabolism. Here, we report the radiosynthesis of two carbon-11 labeled candidate radiotracers (substrate- and inhibitor-based radioligand) for HDAC and their evaluation in non-human primate brain. PET studies showed very low brain uptake and rapid metabolism of both labeled compounds but revealed a surprising enhancement of brain penetration by F for H substitution when comparing one of these to [18F]FAHA. Further structural refinement is needed for the development of brain-penetrant, metabolically stable HDAC radiotracers and to understand the role of fluorine substitution on brain penetration.

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“…[76] HDACs have also been successfully targeted by radiotracers. Three different HDAC radiotracer targets have been described by Aginagalde et al, Hendricks et al, and Zeglis et al [77–79]. If HIV specific HDACs could be identified and targeted, these might facilitate identification, reduction or elimination of latently infected cells.…”

Section: Rational Design Approachmentioning

confidence: 99%

Rational development of radiopharmaceuticals for HIV-1

Lau¹,

Maldarelli²,

Eckelman³

et al. 2014

Nuclear Medicine and Biology

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The global battle against HIV-1 would benefit from a sensitive and specific radiopharmaceutical to localize HIV-infected cells. Ideally, this probe would be able to identify latently infected host cells containing replication competent HIV sequences. Clinical and research applications would include assessment of reservoirs, informing clinical management by facilitating assessment of burden of infection in different compartments, monitoring disease progression and monitoring response to therapy. A “rational” development approach could facilitate efficient identification of an appropriate targeted radiopharmaceutical. Rational development starts with understanding characteristics of the disease that can be effectively targeted and then engineering radiopharmaceuticals to hone in on an appropriate target, which in the case of HIV-1 (HIV) might be an HIV-specific product on or in the host cell, a differentially expressed gene product, an integrated DNA sequence specific enzymatic activity, part of the inflammatory response, or a combination of these. This is different from the current approach that starts with a radiopharmaceutical for a target associated with a disease, mostly from autopsy studies, without a strong rationale for the potential to impact patient care. At present, no targeted therapies are available for HIV latency, although a number of approaches are under study. Here we discuss requirements for a radiopharmaceutical useful in strategies targeting persistently infected cells. The radiopharmaceutical for HIV should be developed based on HIV biology, studied in an animal model and then in humans, and ultimately used in clinical and research settings.

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The synthesis and evaluation of N1-(4-(2-[18F]-fluoroethyl)phenyl)-N8-hydroxyoctanediamide ([18F]-FESAHA), A PET radiotracer designed for the delineation of histone deacetylase expression in cancer

Cited by 17 publications

References 52 publications

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

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

Radionuclide labeling and evaluation of candidate radioligands for PET imaging of histone deacetylase in the brain

Rational development of radiopharmaceuticals for HIV-1

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