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Kinetically Inert MRI/PET Probes with Myeloperoxidase-Triggered Covalent Capture for Quantitative Imaging of Acute
Tiantian Luo1,2, Lu Liu3, Jie Yang1
1Medical Imaging Key Laboratory of Sichuan Province, School of Medical Imaging, North Sichuan Medical College, Nanchong, Sichuan 637000, China.
Abstract:
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 t1/2 = 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.
Insights
Researchers developed a novel manganese chelate, Mn-TyrCDTA, for imaging myeloperoxidase (MPO)-driven inflammation. This agent enables quantitative assessment of oxidative tissue injury by linking enzyme activity to a sustained imaging signal.
Area of Science:
- Biomedical Imaging
- Chemical Biology
- Molecular Imaging
Background:
- Myeloperoxidase (MPO) is a key enzyme in oxidative stress and inflammatory tissue injury.
- Current imaging methods struggle to selectively and sustainably detect MPO activity.
- Developing targeted imaging agents for MPO is crucial for understanding and managing inflammatory diseases.
Purpose of the Study:
- To design and characterize a novel manganese chelate, Mn-TyrCDTA, for MPO-mediated oxidative stress imaging.
- To couple kinetic inertness with MPO-triggered activation and retention for enhanced imaging.
- To validate Mn-TyrCDTA's efficacy in quantitative disease severity stratification.
Main Methods:
- Synthesized Mn-TyrCDTA, a manganese chelate with a rigidified CDTA scaffold and a tyramine-derived phenolic moiety.
- Evaluated kinetic inertness of Mn-TyrCDTA under Zn2+ challenge.
- Assessed MPO/H2O2-mediated oxidation, covalent protein anchoring, and relaxivity enhancement.
- Utilized rat models of acute pancreatitis for in vivo imaging studies.
- Performed complementary 68Ga-TyrCDTA Positron Emission Tomography (PET) studies.
Main Results:
- Mn-TyrCDTA demonstrated 3-fold improved kinetic inertness compared to EDTA-based chelates.
- MPO/H2O2-mediated oxidation led to a 3.6-fold relaxivity enhancement and sustained retention in inflamed tissues.
- In acute pancreatitis models, contrast enhancement strongly correlated with tissue MPO activity (R2 = 0.83).
- 68Ga-TyrCDTA PET showed enzyme-dependent tracer accumulation, with MPO inhibition reducing signal by 85% (R2 = 0.98).
Conclusions:
- Mn-TyrCDTA serves as an effective agent for quantitative imaging of MPO-driven oxidative tissue injury.
- The developed agent enables accurate disease severity stratification in inflammatory conditions.
- This study provides a rational design framework for developing targeted imaging agents for neutrophil-driven inflammation.
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