Targeting MMPS to Image Atherosclerosis

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DESCRIPTION (provided by applicant): The incidence of acute coronary events is associated with acute thrombotic occlusion of the coronary artery and is likely to result from rupture of the atherosclerotic plaque. The disruption of atheromatous plaque is not necessarily associated with severely obstructive lesions, and the likelihood of plaque rupture is better determined by histologic characteristics. The vulnerable plaques usually demonstrate sizable lipid cores, and thin fibrous caps which are intensely infiltrated by mononuclear cells. Inflammation is directly related to metalloproteinase (MMP) expression and activation in the atherosclerotic plaques, and may constitute the causal link between inflammation and plaque vulnerability. Therefore, radionuclide targeting of MMP 1 production and activity may allow noninvasive detection of the plaques susceptible to rupture. In the proposed study, indium-1 1 1 -labeled broad-based inhibitor of metalloproteinases (MPI) will be used for the detection of MMP in experimentally-induced atherosclerotic plaques. In addition, technetium-99m- labeled monocyte chemoattractant protein-I (MCP-1) will be employed for targeting of inflammatory burden in atherosclerotic plaques. MPI peptide has broad inhibitory specificity for MMP 1-3, 7-9 and -13 with high inhibitory coefficients, and radiolabeled peptide selectively determines the extent of MMP expression. On the other hand, radiolabeled recombinant human MCP-1, a monomeric 9-1 5 kD polypeptide, specifically binds to MCP-1 receptors on monocytes/macrophages upregulated during recruitment of these cells to the plaque. Experimental models will include lipid-fed rabbits, and genetically altered animals likely to harbor higher degree of monocytic infiltration or MMP production. In addition, diffuse atherosclerotic disease of coronary and carotid arteries will be studied in diabetic swine. Finally, the data obtained from the experimental studies will be translated to develop a clinical diagnostic tool (as a proof of concept) in patients with recent cerebrovascular accidents. The extent of inflammation and MMP expression in the plaques will be ascertained histopathologically. (End of Abstract)