Targeted Molecular Probes for Atherosclerosis Imaging and Therapy

总结 动脉粥样硬化是一种进行性疾病，其特征是发展为富含脂质的炎性斑块 血管壁内病变。它是包括心肌梗死在内的心血管疾病的潜在基础， 中风和外周动脉疾病。然而，可靠地检测易损斑块并识别 高风险患者是一个挑战。此外，没有成像剂来检测侵蚀斑块， 已知亚型占临床事件的三分之一。趋化因子和趋化因子受体起重要作用 通过指导白细胞运输在动脉粥样硬化从初始化到临床事件中的作用。我们已经开发 趋化因子受体靶向的正电子发射断层扫描（PET）成像剂，并证明了 特异性检测体内单核细胞运输并跟踪斑块进展和消退。进一步 探索这些显像剂的翻译潜力，我们想提出一个研究计划， 开发新型PET示踪剂，有可能识别易损斑块，检测斑块侵蚀等 重要的是跟踪治疗反应以改善患者结果。具体而言，我们将首先优化 设计和合成一系列靶向斑块相关靶点的PET示踪剂，包括CCR 2，CCR 5， CXCR 3、CD 44和TLR 2，以通过受控的放射性标记和规模扩大能力， 放射化学和生物缀合物化学，以及通过改变电荷、表面化学和 聚合物涂层材料。其次，我们将进行体内生物分布研究和PET成像， 动脉粥样硬化进展/消退和并发症小鼠模型，以及兔动脉粥样硬化 评估成像特异性、灵敏度和体内追踪免疫细胞的能力的模型， 与目标表达和斑块特征的相关性。第三，我们将评估 开发了成像探针，以确定治疗反应，以改善结果并与离体 用于将来翻译的人类斑块组织。我们建议提交多个探索性研究新药 申请FDA，并有两个PET示踪剂准备在资助期结束时进行人体试验。的 该研究计划的建立不仅将促进靶向PET示踪剂的开发， 动脉粥样硬化平移成像，而且在NHLBI使命内的其他疾病中也有更广泛的应用。

Summary Atherosclerosis is a progressive disease characterized by the development of lipid-rich, inflammatory plaque lesions within vessel walls. It is the underlying basis of cardiovascular diseases including myocardial infarction, stroke, and peripheral arterial disease. However, the ability to reliably detect the vulnerable plaque and identify high-risk patients has been a challenge. Further, there is no imaging agent to detect the eroded plaques, a less- known subtype accounting for one third of clinical events. Chemokines and chemokine receptors play important roles in atherosclerosis from initialization to clinical event by directing leukocyte trafficking. We have developed chemokine receptor targeted positron emission tomography (PET) imaging agents and demonstrated the specific detection of monocyte trafficking in vivo and track plaque progression and regression. To further explore the potential of these imaging agents for translation, we would like to propose a research program to develop novel PET tracers with potential to identify vulnerable plaques, detect plaque erosion, and more importantly to track the treatment response to improve patient outcome. Specifically, we will firstly optimize the design and synthesis of a portfolio of PET tracers targeting plaque-relevant targets including CCR2, CCR5, CXCR3, CD44, and TLR2 to improve the radiolabeling and scale-up capability through controlled radiochemistry and bioconjugate chemistry, and binding affinities by varying the charge, surface chemistry and polymer coating materials. Secondly, we will perform in vivo biodistribution studies and PET imaging in atherosclerosis progression/regression and complication mouse models, as well as rabbit atherosclerosis models to assess the imaging specificity, sensitivity, and capability to track the immune cells in vivo and correlation with targets expression and plaque characteristics. Thirdly, we will assess the capability of developed imaging probes to determine treatment response for improved outcome and binding to ex vivo human plaque tissue for future translation. We propose to submit multiple exploratory investigational new drug application to FDA and have two PET tracers ready for human trials at the end of grant period. The establishment of this research program will not only promote the development of targeted PET tracers for atherosclerosis translational imaging, but also broader applications in other diseases within the NHLBI mission.