Human myeloperoxidase: a potential target for molecular MR imaging in atherosclerosis.
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.
Chen
John W
JW
Center for Molecular Imagina Research, Massachusetts General Hospital, Charlestown 02129, USA.
Pham
Wellington
W
Weissleder
Ralph
R
Bogdanov
Alexei
A
D001161:Arteriosclerosis / Q000201:enzymology*; D003287:Contrast Media / Q000138:chemical synthesis*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis*; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis*; D009195:Peroxidase / Q000378:metabolism*; D019047:Phantoms, Imaging
D003287:Contrast Media; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; C496989:glycylmethyl DOTA(Gd) 5-hydroxytryptamide; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D009195:Peroxidase