Kinetically Inert MRI/PET Probes with Myeloperoxidase-Triggered Covalent Capture for Quantitative Imaging of Acute...

Myeloperoxidase (MPO)-mediated oxidative stress drives inflammatory tissue injury, yet converting this enzyme activity into a selective and sustained imaging readout remains chemically challenging. To address this limitation, we report Mn-TyrCDTA, a manganese chelate designed to couple kinetic inertness with MPO-triggered activation and retention mechanism. Replacement of a flexible EDTA backbone with a rigidified CDTA scaffold improved the kinetic inertness 3-fold under a Zn²⁺ challenge (dissociation t_1/2 = 61.7 min). Incorporation of a tyramine-derived phenolic moiety enabled MPO/H₂O₂-mediated, one-electron oxidation and covalent protein anchoring, resulting in a 3.6-fold relaxivity enhancement and prolonged inflamed tissue retention. In rat models of acute pancreatitis, contrast enhancement correlated with tissue MPO activity (R² = 0.83), enabling quantitative disease severity stratification. Complementary ⁶⁸Ga-TyrCDTA PET studies demonstrated enzyme-dependent tracer accumulation, and MPO inhibition reduced the imaging signal by 85% (R² = 0.98). These findings establish a rational design framework for the quantitative imaging of neutrophil-driven oxidative tissue injury.