The overall objective of this study it to use Positron Emission Tomography (PET) brain imaging and a radiotracer that measures the epigenetic marker Histone Deacetylase 6 (HDAC6) to examine HDAC6 expression in people with Post-Traumatic Stress Disorder (PTSD), Alcohol Use Disorder (AUD), or concurrent PTSD and AUD with control groups. While there are a large number of studies conducted in preclinical stress and addiction models, these findings have not been translated to people living with these disorders. This study will examine relationships between HDAC6 and clinical variables of interest. Findings could direct treatment development.

Start Date05 Jun 2024

Sponsor / Collaborator

Yale University

100 Clinical Results associated with [18F]Bavarostat

100 Translational Medicine associated with [18F]Bavarostat

100 Patents (Medical) associated with [18F]Bavarostat

Literatures (Medical) associated with [18F]Bavarostat

01 May 2022·The FASEB Journal

Aromatic C‐F Interactions Influence Binding Mode of Inhibitors in HDAC6

Article

Author: Hooker, Jacob ; Christianson, David W. ; Watson, Paris R.

Fluorine is increasingly being incorporated into pharmaceuticals to modulate their physical properties. Furthermore, 18F can be utilized in positron emission tomography (PET) probes for in vivo imaging. Bavarostat is a selective inhibitor of histone deacetylase 6 (HDAC6), and when derivatized with 18F is used to map out HDAC6 localisation within the brain. As HDAC6 is implicated in Alzheimer’s disease due to its function as a Tau deacetylase, it may serve as an effective biomarker for this disease. The active site cavity of HDAC6 contains two phenylalanine residues that form an aromatic crevice, F583 and F643, that engage in offset π‐π interactions with phenylhydroxymate binding groups. Moreover, the fluoroaromatic ring of Bavarostat orientates such that the C–F group binds in the aromatic crevice instead of being exposed to solvent. Structure activity relationships were determined for a series of fluorophenylhydroxymates to inform the design of fluorinated inhibitors of HDAC6 as well PET probes. Our studies show the aromatic crevice of HDAC6 preferentially binds C–F groups in this series of inhibitors. The inhibitors show differences in zinc binding orientations, likely due to the electronic influence of fluorine on the hydroxymate zinc‐binding group.

01 Apr 2020·ACS Chemical Neuroscience

Translation of HDAC6 PET Imaging Using [¹⁸F]EKZ-001–cGMP Production and Measurement of HDAC6 Target Occupancy in Nonhuman Primates

Article

Author: Bleeser, Tom ; Koole, Michel ; Celen, Sofie ; Hightower, Baileigh G. ; Serdons, Kim ; Gilbert, Tonya M. ; Schroeder, Frederick A. ; Vanduffel, Wim ; Rokka, Johanna ; Kranz, Janice E. ; Hooker, Jacob M. ; Rahal, Dania ; Hu, Jiyun ; Cawthorne, Christopher J. ; Wagner, Florence F. ; Beyzavi, Hudson ; Bormans, Guy ; Van Laere, Koen ; Vermeulen, Isabeau

Histone deacetylase 6 (HDAC6) is a multifunctional cytoplasmic enzyme involved in diverse cellular processes such as intracellular transport and protein quality control. Inhibition of HDAC6 can alleviate defects in cell and rodent models of certain diseases, particularly neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis. However, while HDAC6 represents a potentially powerful therapeutic target, development of effective brain-penetrant HDAC6 inhibitors remains challenging. Recently, [¹⁸F]EKZ-001 ([¹⁸F]Bavarostat), a brain-penetrant positron emission tomography (PET) radioligand with high affinity and selectivity toward HDAC6, was developed and evaluated preclinically for its ability to bind HDAC6. Herein, we describe the efficient and robust fully automated current Good Manufacturing Practices (cGMP) compliant production method. [¹⁸F]EKZ-001 quantification methods were validated in nonhuman primates (NHP) using full kinetic modeling, and [¹⁸F]EKZ-001 PET was applied to compare dose-occupancy relationships between two HDAC6 inhibitors, EKZ-317 and ACY-775. [¹⁸F]EKZ-001 is cGMP produced with an average decay-corrected radiochemical yield of 14% and an average molar activity of 204 GBq/μmol. We demonstrate that a two-tissue compartmental model and Logan graphical analysis are appropriate for [¹⁸F]EKZ-001 PET quantification in NHP brain. Blocking studies show that the novel compound EKZ-317 achieves higher target occupancy than ACY-775. This work supports the translation of [¹⁸F]EKZ-001 PET for first-in-human studies.

27 Sep 2017·ACS Central ScienceQ1 · CHEMISTRY

HDAC6 Brain Mapping with [¹⁸F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination

Q1 · CHEMISTRY

ArticleOA

Author: Haggarty, Stephen J. ; Campbell, Arthur J. ; Wagner, Florence F. ; Riley, Misha M. ; Schroeder, Frederick A. ; Zhao, Wen-Ning ; Ritter, Tobias ; Hooker, Jacob M. ; Strebl, Martin G. ; Chindavong, Peter S. ; Morin, Thomas M.

Histone deacetylase 6 (HDAC6) function and dysregulation have been implicated in the etiology of certain cancers and more recently in central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. HDAC6-selective inhibitors have therapeutic potential, but in the CNS drug space the development of highly brain penetrant HDAC inhibitors has been a persistent challenge. Moreover, no tool exists to directly characterize HDAC6 and its related biology in the living human brain. Here, we report a highly brain penetrant HDAC6 inhibitor, Bavarostat, that exhibits excellent HDAC6 selectivity (>80-fold over all other Zn-containing HDAC paralogues), modulates tubulin acetylation selectively over histone acetylation, and has excellent brain penetrance. We further demonstrate that Bavarostat can be radiolabeled with ¹⁸F by deoxyfluorination through in situ formation of a ruthenium π-complex of the corresponding phenol precursor: the only method currently suitable for synthesis of [¹⁸F]Bavarostat. Finally, by using [¹⁸F]Bavarostat in a series of rodent and nonhuman primate imaging experiments, we demonstrate its utility for mapping HDAC6 in the living brain, which sets the stage for first-in-human neurochemical imaging of this important target.

100 Deals associated with [18F]Bavarostat

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Preclinical	Belgium	Eikonizo Therapeutics, Inc.	08 Jul 2020
Motor Neuron Disease	Preclinical	Belgium	Eikonizo Therapeutics, Inc.	08 Jul 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


SNMMI2020	Not Applicable	-	-	ACY-775	ocelmhgofa(bdtrpzfhip) = rfpxehczbr xtomsmmhfp (inftxclslh ) View more	-	15 May 2020
				[18F]Bavarostat	fckspdnrnm(xbvvjhrrrc) = xexlnzzezv ofawzmgrok (qpwwgktdcc, 10.7)

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