CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

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Project Abstract Abdominal aortic aneurysm (AAA) represents a life-threatening degenerative vascular disease. AAAs usually remain asymptomatic until they rupture, leading to high mortality. AAA is more prevalent in men over the age of 65 years-old; however, AAA rupture occurs more often in women. The clinical imaging of AAAs largely centers around measurement of AAA diameter, which is a poor marker for rupture prediction. There is an unmet clinical need for a molecular imaging strategy to phenotype AAA patients for risk stratification. Monocyte chemotactic protein-1/Chemokine (C-C motif) receptor 2 (MCP-1/CCR2) axis plays an important role in the pathogenesis of AAAs by mediating the recruitment of inflammatory monocytes and infiltration of macrophages, resulting in the degradation of aortic wall elastin and collagen. We have developed a CCR2-targeting radiotracer, 64Cu-DOTA- ECL1i, for positron emission tomography (PET) imaging of CCR2+ pro-inflammatory monocytes/macrophages and have demonstrated the specific detection of CCR2+ cells in patients with cardiovascular diseases. In murine AAA models, 64Cu-DOTA-ECL1i PET demonstrated specific radiotracer uptake within the AAA wall that correlated with sensitive detection of variations in CCR2+ cell populations. Marked elevation of radiotracer uptake in rupture-prone AAAs demonstrated the potential of this radiotracer to assess AAA vulnerability. Moreover, administration of a CCR2 inhibitor significantly decreased AAA progression and inhibited associated rupture. We propose to assess CCR2+ inflammatory processes associated with AAA development and exploit these processes as therapeutic targets in rodent AAA models, while exploring targeted CCR2 PET imaging in AAA patients, by achieving the following specific aims. Aim 1. Assess 64Cu-DOTA-ECL1i PET for the characterization of CCR2+ cell activity during AAA development and rupture in pre-clinical models. Aim 1A. Correlate 64Cu-DOTA-ECL1i PET uptake with CCR2+ immune cell activity in vulnerable AAAs and changes in the histopathological properties of murine AAA rupture models. Aim 1B. Optimize CCR2 antagonist treatment regimens in murine AAA models and assess 64Cu-DOTA-ECL1i PET as a companion diagnostic to determine treatment response. Aim 2. Determine the relationship between 64Cu-DOTA-ECL1i binding and CCR2+ cellular composition using bio-banked human AAA specimens. Aim 2A. Determine the binding characteristics of 64Cu- DOTA-ECL1i in ex vivo human AAA specimens and correlate these with associated histopathological features. Aim 2B. Determine the relationship between 64Cu-DOTA-ECL1i tissue autoradiography, regional CCR2 gene expression, cytokine profiles, and local matrix metalloproteinase activity. Aim 3. Assess the performance of 64Cu- DOTA-ECL1i PET/CT to detect CCR2+ inflammatory cells in the human aorta. Aim 3A. Assess 64Cu-DOTA- ECL1i imaging characteristics in AAA patients undergoing open repair and control, healthy volunteers to determine the relationship between tracer uptake and molecular characterization of prospectively collected AAA tissues. Aim3B. Assess the imaging reproducibility of 64Cu-DOTA-ECL1i PET/CT imaging in AAA patients.