Noninvasive targeted imaging of matrix metalloproteinase activation in a murine model of postinfarction remodeling

Background: Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this process serially are needed. Methods and Results: MMP-targeted radiotracers were developed that displayed selective binding kinetics to the active MMP catalytic domain. Initial nonimaging studies were performed with a In-111-labeled MMP-targeted radiotracer (In-111-RP782) and negative control compound (In-111-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of In-111-RP782 was demonstrated within the MI by microautoradiography. A 334 +/- 44% increase (P < 0.001 versus Ctrl) in relative retention of In-111-RP782 was confirmed by gamma well counting of myocardium. Subsequent high-resolution dual-isotope planar and hybrid micro-single-photon emission computed tomography/CT imaging studies with an analogous Tc-99m-labeled MMP-targeted radiotracer (Tc-99m-RP805) and Tl-201 demonstrated favorable biodistribution and clearance kinetics of Tc-99m-RP805 for in vivo cardiac imaging, with robust retention 1 to 3 weeks after MI in regions of decreased 201Tl perfusion. Gamma well counting yielded a similar approximate to 300% increase in relative myocardial retention of Tc-99m-RP805 in MI regions (Ctrl, 102 +/- 9%; 1 week, 351 +/- 77%; 2 weeks, 291 +/- 45%; 3 weeks, 292 +/- 41%; P < 0.05 versus Ctrl). Myocardial uptake in the MI region was also significantly increased approximate to 5-fold when expressed as percentage injected dose per gram tissue. There was also a significant 2-fold increase in myocardial activity in remote regions relative to control mice, suggesting activation of MMPs in regions remote from the MI. Conclusions: This novel noninvasive targeted MMP radiotracer imaging approach holds significant diagnostic potential for in vivo localization of MMP activation and tracking of MMP-mediated post-MI remodeling.