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.


RESULTS
MMP-targeted radiotracers were developed that displayed selective binding kinetics to the active MMP catalytic domain. Initial nonimaging studies were performed with a (111)In-labeled MMP-targeted radiotracer ((111)In-RP782) and negative control compound ((111)In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of (111)In-RP782 was demonstrated within the MI by microautoradiography. A 334+/-44% increase (P<0.001 versus Ctrl) in relative retention of (111)In-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 approximately 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 approximately 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.
Su
Haili
H
Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520-8017, USA.
Spinale
Francis G
FG
Dobrucki
Lawrence W
LW
Song
James
J
Hua
Jing
J
Sweterlitsch
Sarah
S
Dione
Donald P
DP
Cavaliere
Patti
P
Chow
Conroy
C
Bourke
Brian N
BN
Hu
Xiao-Yu
XY
Azure
Michael
M
Yalamanchili
Padmaja
P
Liu
Richard
R
Cheesman
Edward H
EH
Robinson
Simon
S
Edwards
D Scott
DS
Sinusas
Albert J
AJ
D000818:Animals; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000000981:diagnostic imaging*; D011877:Radionuclide Imaging / Q000379:methods*; D020257:Ventricular Remodeling / Q000502:physiology
D020782:Matrix Metalloproteinases