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

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. In conclusion, 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.
Authors:
 [1] ;  [2] ;  [3] ; ORCiD logo [4] ;  [4] ;  [3] ;  [5] ;  [3] ;  [2] ; ORCiD logo [6] ; ORCiD logo [7]
  1. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Harvard Univ., Cambridge, MA (United States)
  2. Broad Institute of MIT and Harvard, Cambridge, MA (United States)
  3. Massachusetts General Hospital, Harvard Medical School, Boston, MA (United States)
  4. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States)
  5. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Tufts Univ., Medford, MA (United States)
  6. Harvard Univ., Cambridge, MA (United States); Massachusetts General Hospital, Boston, MA (United States); Max-Planck-Institut fur Kohlenforschung, Mulheim an der Ruhr (Germany)
  7. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Massachusetts General Hospital, Boston, MA (United States)
Publication Date:
Grant/Contract Number:
SC0008430
Type:
Published Article
Journal Name:
ACS Central Science
Additional Journal Information:
Journal Volume: 3; Journal Issue: 9; Journal ID: ISSN 2374-7943
Publisher:
American Chemical Society (ACS)
Research Org:
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1378833
Alternate Identifier(s):
OSTI ID: 1417628

Strebl, Martin G., Campbell, Arthur J., Zhao, Wen -Ning, Schroeder, Frederick A., Riley, Misha M., Chindavong, Peter S., Morin, Thomas M., Haggarty, Stephen J., Wagner, Florence F., Ritter, Tobias, and Hooker, Jacob M.. HDAC6 Brain Mapping with [18 F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination. United States: N. p., Web. doi:10.1021/acscentsci.7b00274.
Strebl, Martin G., Campbell, Arthur J., Zhao, Wen -Ning, Schroeder, Frederick A., Riley, Misha M., Chindavong, Peter S., Morin, Thomas M., Haggarty, Stephen J., Wagner, Florence F., Ritter, Tobias, & Hooker, Jacob M.. HDAC6 Brain Mapping with [18 F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination. United States. doi:10.1021/acscentsci.7b00274.
Strebl, Martin G., Campbell, Arthur J., Zhao, Wen -Ning, Schroeder, Frederick A., Riley, Misha M., Chindavong, Peter S., Morin, Thomas M., Haggarty, Stephen J., Wagner, Florence F., Ritter, Tobias, and Hooker, Jacob M.. 2017. "HDAC6 Brain Mapping with [18 F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination". United States. doi:10.1021/acscentsci.7b00274.
@article{osti_1378833,
title = {HDAC6 Brain Mapping with [18 F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination},
author = {Strebl, Martin G. and Campbell, Arthur J. and Zhao, Wen -Ning and Schroeder, Frederick A. and Riley, Misha M. and Chindavong, Peter S. and Morin, Thomas M. and Haggarty, Stephen J. and Wagner, Florence F. and Ritter, Tobias and Hooker, Jacob M.},
abstractNote = {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. In conclusion, 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.},
doi = {10.1021/acscentsci.7b00274},
journal = {ACS Central Science},
number = 9,
volume = 3,
place = {United States},
year = {2017},
month = {9}
}