Published Online
on November 7, 2005

A more recent version of this article appeared on November 15, 2005

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Submitted on September 9, 2004
Revised on August 15, 2005
Accepted on August 22, 2005

Noninvasive Targeted Imaging of Matrix Metalloproteinase Activation in a Murine Model of Postinfarction Remodeling

Haili Su MD, Francis G. Spinale MD, PhD, Lawrence W. Dobrucki PhD, James Song MD, Jing Hua MD, Sarah Sweterlitsch BS, Donald P. Dione BS, Patti Cavaliere BS, Conroy Chow BS, Brian N. Bourke MS, Xiao-Yu Hu MD, Michael Azure PhD, Padmaja Yalamanchili PhD, Richard Liu PhD, Edward H. Cheesman PhD, Simon Robinson PhD, D. Scott Edwards PhD, and Albert J. Sinusas MD^*

From the Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, and Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Conn (H.S., L.W.D., J.S., J.H., D.P.D., P.C., C.C., B.N.B., X.-Y.H., A.J.S.); the Medical University of South Carolina and Ralph H. Johnson Veteran’s Affairs Medical Center, Charleston, SC (F.G.S., S.S.); and Bristol-Myers Squibb Medical Imaging, North Billerica, Mass (M.A., P.Y., R.L., E.H.C., S.R., D.S.E.).

^* To whom correspondence should be addressed. E-mail: albert.sinusas{at}yale.edu.

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 ¹¹¹In-labeled MMP-targeted radiotracer (¹¹¹In-RP782) and negative control compound (¹¹¹In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of ¹¹¹In-RP782 was demonstrated within the MI by microautoradiography. A 334±44% increase (P<0.001 versus Ctrl) in relative retention of ¹¹¹In-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 ^99mTc-labeled MMP-targeted radiotracer (^99mTc-RP805) and ²⁰¹Tl demonstrated favorable biodistribution and clearance kinetics of ^99mTc-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 300% increase in relative myocardial retention of ^99mTc-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 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.

Key words: myocardial infarction • metalloproteinases • remodeling • radionuclide imaging

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