Imaging of innate immunity activation in vivo with a redox-tuned PET reporter
NATURE BIOTECHNOLOGY(2022)
Abstract
High-redox-potential reactive oxygen species and reactive nitrogen species (ROS/RNS), generated by NADPH oxidase-2 (NOX2), myeloperoxidase (MPO) and related enzymes, are key effector molecules of innate immunity. High-redox-potential radicals are difficult to distinguish by imaging from less potent ROS/RNS functioning as background biological signaling molecules. Here we present 4-[ 18 F]fluoro-1-naphthol ([ 18 F]4FN), a redox-tuned radiopharmaceutical that selectively binds proteins and cells when oxidized by products of human MPO plus H 2 O 2 , but not H 2 O 2 alone, and can be detected using positron emission tomography (PET). Activating HL-60 neutrophil-like human cells with phorbol ester (PMA) caused [ 18 F]4FN retention five-fold over unstimulated cells. An MPO-specific inhibitor (4-ABAH) blocked cellular retention by more than 95%. [ 18 F]4FN PET/CT imaging discriminated inflammatory foci in vivo in three murine models of activated innate immunity: endotoxin-induced toxic shock, PMA-induced contact dermatitis and lipopolysaccharide-induced ankle arthritis. 4-ABAH and Cybb −/− (Nox2 −/− ) gene deletion strongly abrogated [ 18 F]4FN retention in vivo. Thus, [ 18 F]4FN shows promise as a robust reporter of innate immunity activation by PET/CT.
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Key words
Biomedical materials,Diagnostic markers,Drug discovery and development,Life Sciences,general,Biotechnology,Biomedicine,Agriculture,Biomedical Engineering/Biotechnology,Bioinformatics
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