Submitted on August 10, 2007
Accepted on March 5, 2008
Targeted Imaging of Hypoxia-Induced Integrin Activation in
Myocardium Early After Infarction
Leszek Kalinowski1, Lawrence Wawrzyniec Dobrucki2, David F. Meoli3, Donald P. Dione2, Mehran M. Sadeghi3, Joseph A. Madri4, and Albert J. Sinusas5*
1 Department of Clinical Chemistry and Biochemistry, Medical University of Gdansk, Gdansk, Poland; Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States
2 Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States
3 Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven,, Connecticut, United States
4 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States
5 Experimental Nuclear Cardiology Laboratory, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven,, Connecticut, United States; Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut, United States
* To whom correspondence should be addressed. E-mail: albert.sinusas{at}yale.edu.
The 
v
3-integrin is expressed in angiogenic vessels in response to hypoxia, and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of non-invasively tracking hypoxia-induced v3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies. A novel 111In-labeled radiotracer targeted at the v3-integrin (111In-RP748), was used to localize regions of hypoxia-induced angiogenesis early after infarct. In rodent studies, the specificity of 111In-RP748 for v3-integrin was confirmed with a negative control compound (111In-RP790) and regional uptake of these compounds correlated with 201Tl perfusion and a 99mTc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only 111In-RP748 was selectively retained in infarcted regions with reduced 201Tl perfusion, and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of 111In-RP748 was assessed using in vivo SPECT, ex vivo planar imaging, and gamma well-counting of myocardial tissue, and correlated with 99mTc-sestamibi perfusion. Dual-radiotracer in vivo SPECT imaging of 111In-RP748 and 99mTc-sestamibi provided visualization of 111In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial 111In-RP748 retention was associated with histological evidence of v3-integrin activation/expression in infarct region. 111In-RP748 imaging provides a novel non-invasive approach for evaluation of hypoxia-induced v3-integrin activation in myocardium early after infarction, and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.
