Highly Efficient Activatable MRI Probe to Sense Myeloperoxidase Activity

Wang, Cuihua and Cheng, David and Jalali Motlagh, Negin and Kuellenberg, Enrico G. and Wojtkiewicz, Gregory R. and Schmidt, Stephen P. and Stocker, Roland and Chen, John W. (2021) Highly Efficient Activatable MRI Probe to Sense Myeloperoxidase Activity. Journal of Medicinal Chemistry, 64 (9). pp.5874-5885. ISSN 0022-2623

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Link to published document: http://doi.org/10.1021/acs.jmedchem.1c00038

Abstract

Myeloperoxidase (MPO) is a key component of innate immunity but can damage tissues when secreted abnormally. We developed a new generation of a highly efficient MPO-activatable MRI probe (heMAMP) to report MPO activity. heMAMP has improved Gd stability compared to bis-5-HT-Gd-DTPA (MPO-Gd) and demonstrates no significant cytotoxicity. Importantly, heMAMP is more efficiently activated by MPO compared to MPO-Gd, 5HT-DOTA(Gd), and 5HT-DOTAGA-Gd. Molecular docking simulations revealed that heMAMP has increased rigidity via hydrogen bonding intramolecularly and improved binding affinity to the active site of MPO. In animals with subcutaneous inflammation, activated heMAMP showed a 2-3-fold increased contrast-to-noise ratio (CNR) compared to activated MPO-Gd and 4-10 times higher CNR compared to conventional DOTA-Gd. This increased efficacy was further confirmed in a model of unstable atherosclerotic plaque where heMAMP demonstrated a comparable signal increase and responsiveness to MPO inhibition at a 3-fold lower dosage compared to MPO-Gd, further underscoring heMAMP as a potential translational candidate.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 31 Jul 2021 05:53
Last Modified: 31 Jul 2021 05:53
URI: http://eprints.victorchang.edu.au/id/eprint/1106

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