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Title: Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance

Abstract

Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [11C]Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [11C]Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and non-human primates. Here, the study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life.

Authors:
 [1];  [2];  [2];  [3];  [2];  [2];  [2];  [2]
+ Show Author Affiliations
  1. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Harvard Univ., Cambridge, MA (United States)
  2. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States)
  3. Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States); Harvard Medical School, Belmont, MA (United States)
Publication Date:
Research Org.:
Massachusetts General Hospital and Harvard Medical School, Charlestown, MA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1466781
Grant/Contract Number:  
SC0008430
Resource Type:
Accepted Manuscript
Journal Name:
ACS Chemical Neuroscience
Additional Journal Information:
Journal Volume: 7; Journal Issue: 5; Journal ID: ISSN 1948-7193
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Histone Deacetylase; Positron Emission Tomography; Fluorine; Brain Penetrance; Epigenetics; Blood-Brain Barrier

Citation Formats

Strebl, Martin G., Wang, Changning, Schroeder, Frederick A., Placzek, Michael S., Wey, Hsiao -Ying, Van de Bittner, Genevieve C., Neelamegam, Ramesh, and Hooker, Jacob M. Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance. United States: N. p., 2015. Web. doi:10.1021/acschemneuro.5b00297.
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Strebl, Martin G., Wang, Changning, Schroeder, Frederick A., Placzek, Michael S., Wey, Hsiao -Ying, Van de Bittner, Genevieve C., Neelamegam, Ramesh, & Hooker, Jacob M. Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance. United States. https://doi.org/10.1021/acschemneuro.5b00297
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Strebl, Martin G., Wang, Changning, Schroeder, Frederick A., Placzek, Michael S., Wey, Hsiao -Ying, Van de Bittner, Genevieve C., Neelamegam, Ramesh, and Hooker, Jacob M. Wed . "Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance". United States. https://doi.org/10.1021/acschemneuro.5b00297. https://www.osti.gov/servlets/purl/1466781.
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@article{osti_1466781,
title = {Development of a Fluorinated Class-I HDAC Radiotracer Reveals Key Chemical Determinants of Brain Penetrance},
author = {Strebl, Martin G. and Wang, Changning and Schroeder, Frederick A. and Placzek, Michael S. and Wey, Hsiao -Ying and Van de Bittner, Genevieve C. and Neelamegam, Ramesh and Hooker, Jacob M.},
abstractNote = {Despite major efforts, our knowledge about many brain diseases remains remarkably limited. Epigenetic dysregulation has been one of the few leads toward identifying the causes and potential treatments of psychiatric disease over the past decade. A new positron emission tomography radiotracer, [11C]Martinostat, has enabled the study of histone deacetylase in living human subjects. A unique property of [11C]Martinostat is its profound brain penetrance, a feature that is challenging to engineer intentionally. In order to understand determining factors for the high brain-uptake of Martinostat, a series of compounds was evaluated in rodents and non-human primates. Here, the study revealed the major structural contributors to brain uptake, as well as a more clinically relevant fluorinated HDAC radiotracer with comparable behavior to Martinostat, yet longer half-life.},
doi = {10.1021/acschemneuro.5b00297},
journal = {ACS Chemical Neuroscience},
number = 5,
volume = 7,
place = {United States},
year = {Wed Dec 16 00:00:00 EST 2015},
month = {Wed Dec 16 00:00:00 EST 2015}
}
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https://doi.org/10.1021/acschemneuro.5b00297
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    Works referencing / citing this record:

    Fluorine-18 labelled building blocks for PET tracer synthesis
    journal, January 2017

    • van der Born, Dion; Pees, Anna; Poot, Alex J.
    • Chem. Soc. Rev., Vol. 46, Issue 15
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    Radiosynthesis and preliminary evaluation of an 18 F-labeled tubastatin A analog for PET imaging of histone deacetylase 6
    journal, January 2020

    • Tago, Tetsuro; Toyohara, Jun; Ishii, Kenji
    • Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 63, Issue 2
    • DOI: 10.1002/jlcr.3823

    Neuroimaging Biomarkers for Alzheimer’s Disease
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    Molecular Imaging of Hydrolytic Enzymes Using PET and SPECT
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