Evaluation of myocardial matrix metalloproteinase (MMP) mediated post-MI remodeling with a novel radiolabeled MMP inhibitor

Abstract Background: Myocardial matrix metalloproteinases (MMPs) play an important role in post myocardial infarction (MI) left ventricular (LV) remodeling. The administration of MMP inhibitors may prevent post MI remodeling. The use of a radiolabeled MMP inhibitor targeted at MMPs could provide a novel approach for evaluation of the temporal changes in MMP activation and localization post-MI, which could guide therapy. Methods: A 111 In-labeled MMP targeted compound (RP782, 0.77±0.05 mCi) and the enantiomer negative control compound RP788 (1.04±0.02 mCi) were injected into control mice (n=5 and n=4, respectively) and mice (n=10 and n=4, respectively) at 1wk following surgical-induced MI. Hearts were excised 90–105 min post injection, and filled with dental molding material for sectioning. One short axis slice was frozen and 15 μm sections cut for microautoradiography and in situ zymography. Other slices were cut for gamma well counting. Myocardial RP782 and RP788 activity within MI area was expressed as %non-ischemic (%NI). Results: Microautoradiography demonstrated increased RP782 retention within MI region, although RP788 did not localize to MI region. Gamma well counting revealed a significent increase in RP782 activity in MI regions of post-MI group compared with control group (367±84%NI vs 91±6%NI, p Conclusion: In a murine model of post-MI remodeling, there was over a 3-fold increase in myocardial retention of a novel MMP targeted radiotracer (RP782) within the MI regions associated with increased MMP activation. This MMP targeted radiotracer could be used for evaluating the temporal changes in MMP activation and help direct new therapies directed at reducing MMP mediated post-MI remodeling.