2. Academic Validation
  3. HDAC6 Brain Mapping with [18F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination

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

  • ACS Cent Sci. 2017 Sep 27;3(9):1006-1014. doi: 10.1021/acscentsci.7b00274.
Martin G Strebl 1 2,  Arthur J Campbell 3,  Wen-Ning Zhao 4 5,  Frederick A Schroeder 1,  Misha M Riley 1,  Peter S Chindavong 4 5,  Thomas M Morin 1 6,  Stephen J Haggarty 4 5,  Florence F Wagner 3,  Tobias Ritter 2 7 8,  Jacob M Hooker 1 7
Affiliations

Affiliations

  • 1 Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, United States.
  • 2 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, United States.
  • 3 Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, Massachusetts 02142, United States.
  • 4 Chemical Neurobiology Laboratory, Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 5 Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, United States.
  • 6 Tufts University, 419 Boston Avenue, Medford, Massachusetts 02155, United States.
  • 7 Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts 02144, United States.
  • 8 Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim an der Ruhr, Germany.
PMID: 28979942 DOI: 10.1021/acscentsci.7b00274
Abstract

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.

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