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Self‐Immolative Activation of β‐Galactosidase‐Responsive Probes for In Vivo MR Imaging in Mouse Models
Author(s) -
Lilley Laura M.,
Kamper Sarah,
Caldwell Michael,
Chia Zer Keen,
Ballweg David,
Vistain Luke,
Krimmel Jeffrey,
Mills Teresa Anne,
MacRenaris Keith,
Lee Paul,
Waters Emily Alexandria,
Meade Thomas J.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201909933
Subject(s) - chemistry , carboxylate , ligand (biochemistry) , intramolecular force , linker , in vivo , enzyme , intermolecular force , stereochemistry , biophysics , combinatorial chemistry , molecule , biochemistry , receptor , organic chemistry , microbiology and biotechnology , computer science , biology , operating system
Abstract Our lab has developed a new series of self‐immolative MR agents for the rapid detection of enzyme activity in mouse models expressing β‐galactosidase (β‐gal). We investigated two molecular architectures to create agents that detect β‐gal activity by modulating the coordination of water to Gd III . The first is an intermolecular approach, wherein we designed several structural isomers to maximize coordination of endogenous carbonate ions. The second involves an intramolecular mechanism for q modulation. We incorporated a pendant coordinating carboxylate ligand with a 2, 4, 6, or 8 carbon linker to saturate ligand coordination to the Gd III ion. This renders the agent ineffective. We show that one agent in particular (6‐C pendant carboxylate) is an extremely effective MR reporter for the detection of enzyme activity in a mouse model expressing β‐gal.

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