A positron emission tomography imaging probe selectively targeting the BD1 bromodomain and extra-terminal domain
The two tandem bromodomains of BET (bromodomain and extra-terminal domain) proteins (BD1 and BD2) may play distinct and critical roles in neurological diseases. To better understand the underlying mechanisms of the BD1 bromodomain and facilitate brain permeable domain-selective inhibitor development...
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Published in | Chemical communications (Cambridge, England) Vol. 58; no. 69; pp. 9654 - 9657 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
CAMBRIDGE
Royal Soc Chemistry
25.08.2022
Royal Society of Chemistry |
Subjects | |
Online Access | Get full text |
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Summary: | The two tandem bromodomains of BET (bromodomain and extra-terminal domain) proteins (BD1 and BD2) may play distinct and critical roles in neurological diseases. To better understand the underlying mechanisms of the BD1 bromodomain and facilitate brain permeable domain-selective inhibitor development, we describe here the development of the first BET BD1 positron emission tomography (PET) radioligand [
11
C]
1a
. Compound
1a
was tested to possess potent binding affinities and good selectivity (>20-fold over BD2) for BD1 bromodomains of BRD2 (
K
d
= 25 nM), BRD3 (
K
d
= 24 nM), and BRD4 (
K
d
= 19 nM). Physicochemical characterization of
1a
indicated the brain permeability and specific binding. [
11
C]
1a
was radiosynthesized in a good radiochemical yield (RCY: 25-30%) and molar activity (258 GBq μmol
−1
). The PET imaging studies of [
11
C]1a in mice showed moderate brain uptake (with peak SUV = 0.7) and binding specificity. Furthermore, [
11
C]
1a
demonstrated translational potential in the non-human primate (NHP) PET imaging study, which sets the stage for clinical translation.
Development of a novel brain-permeable PET probe for BET BD1 bromodomain imaging. |
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Bibliography: | https://doi.org/10.1039/d2cc03785h Electronic supplementary information (ESI) available. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1359-7345 1364-548X |
DOI: | 10.1039/d2cc03785h |