Human myeloperoxidase: a potential target for molecular MR imaging in atherosclerosis
John W Chen1, Wellington Pham, Ralph Weissleder
1Center for Molecular Imagina Research, Massachusetts General Hospital, Charlestown 02129, USA.
Abstract:
Plaque rupture in atherosclerotic disease is the major cause of morbidity and correlates well with myeloperoxidase (MPO) secretion by activated neutrophils and macrophages in humans. We hypothesized that paramagnetic electron donor compounds that rapidly oxidize and polymerize in the presence of MPO could be designed to enable imaging of local MPO activity levels in arterial segments at risk. Several potential substrates for MPO were synthesized and tested. One lead compound consisting of a covalent conjugate of GdDOTA and serotonin (3-(2-aminoethyl)-5-hydroxyindole) was efficiently polymerized in the presence of human neutrophil MPO resulting in a 70-100% increase in proton relaxivity. As a result, we were able to demonstrate MPO activity in enzyme solutions and in a model tissue-like system. These studies suggest that activatable paramagnetic MR imaging agents can be used to directly image MPO activity.
Insights
New MRI contrast agents can now detect myeloperoxidase (MPO) activity, a key marker of atherosclerotic plaque rupture. This breakthrough allows for direct imaging of MPO levels in arteries at risk.
Area of Science:
- Biomedical Imaging
- Molecular Imaging
- Cardiovascular Research
Background:
- Plaque rupture in atherosclerotic disease is a primary cause of morbidity.
- Myeloperoxidase (MPO) secretion by activated immune cells correlates with plaque rupture risk.
- Current imaging methods lack direct assessment of local MPO activity.
Purpose of the Study:
- To design and synthesize novel paramagnetic compounds activatable by MPO.
- To enable direct imaging of local MPO activity levels in at-risk arterial segments.
- To develop activatable contrast agents for molecular MRI of atherosclerosis.
Main Methods:
- Synthesis of paramagnetic electron donor compounds.
- Testing MPO-mediated polymerization and relaxivity changes.
- Evaluation in enzyme solutions and a tissue-like model system.
Main Results:
- A lead compound, GdDOTA-serotonin conjugate, efficiently polymerized with human neutrophil MPO.
- Polymerization resulted in a significant 70-100% increase in proton relaxivity.
- Demonstrated successful detection of MPO activity in vitro and in a model system.
Conclusions:
- Activatable paramagnetic MRI agents can be developed to target MPO.
- Direct imaging of MPO activity is feasible using these novel agents.
- This approach holds potential for improved assessment of atherosclerotic disease.
