CCR2 Targeted Molecular Imaging and Treatment of Abdominal Aortic Aneurysms

项目摘要 腹主动脉瘤（AAA）是一种危及生命的退行性血管疾病。AA通常 在破裂前一直无症状，导致高死亡率。AAA在年龄超过30岁的男性中更为普遍。 65岁;然而，AAA破裂更常见于女性。AAAs的临床影像主要集中在 AAA直径的测量值，这是破裂预测的不良标志。存在未满足的临床 需要一种分子成像策略来对AAA患者进行表型分析，以进行风险分层。单核细胞趋化 蛋白1/趋化因子受体2（MCP-1/CCR 2）轴在肿瘤的发病机制中起重要作用， AAAs通过介导炎性单核细胞的募集和巨噬细胞的浸润， 主动脉壁弹性蛋白和胶原的降解。我们开发了一种靶向CCR 2的放射性示踪剂，64 Cu-DOTA， ECL 1 i，用于CCR 2+促炎单核细胞/巨噬细胞的正电子发射断层扫描（PET）成像 并且已经证明了在心血管疾病患者中CCR 2+细胞的特异性检测。小鼠 AAA模型，64 Cu-DOTA-ECL 1 i PET显示AAA壁内的特异性放射性示踪剂摄取， 与CCR 2+细胞群体中变异的灵敏检测相关。放射性示踪剂显著升高 在破裂倾向AAA中的吸收证明了这种放射性示踪剂评估AAA脆弱性的潜力。 此外，CCR 2抑制剂的给药显著降低AAA进展，并抑制相关的 破裂我们建议评估与AAA发展相关的CCR 2+炎症过程， 这些过程作为啮齿动物AAA模型的治疗靶点，同时探索靶向CCR 2 PET成像， AAA患者，通过实现以下具体目标。目标1.评估64 Cu-DOTA-ECL 1 i PET的 在临床前模型中AAA发展和破裂期间CCR 2+细胞活性的表征。目标1A。 将64 Cu-DOTA-ECL 1 i PET摄取与易感AAA中的CCR 2+免疫细胞活性以及 小鼠AAA破裂模型的组织病理学特性。目标1B。优化CCR 2拮抗剂治疗 方案，并评估64 Cu-DOTA-ECL 1 i PET作为伴随诊断，以确定 治疗反应。目标2.确定64 Cu-DOTA-ECL 1 i结合与CCR 2+细胞 使用生物库中的人AAA标本测定组合物。目标2A。确定64 Cu-的结合特性 DOTA-ECL 1 i在离体人AAA标本中的应用，并将这些与相关的组织病理学特征相关联。 目标2B确定64 Cu-DOTA-ECL 1 i组织放射自显影与区域CCR 2基因的关系 表达、细胞因子谱和局部基质金属蛋白酶活性。目标3：评估64 Cu的性能- DOTA-ECL 1 i PET/CT用于检测人主动脉中的CCR 2+炎性细胞。目标3A。评估64 Cu-DOTA- 接受开放修复术的AAA患者和对照健康志愿者的ECL 1 i成像特征， 确定示踪剂摄取与前瞻性收集的AAA的分子表征之间的关系 组织中目标3B评估64 Cu-DOTA-ECL 1 i PET/CT成像在AAA患者中的成像再现性。

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.