Targeted Molecular Probes for Atherosclerosis Imaging and Therapy

摘要 动脉粥样硬化是一种进行性疾病，其特征是形成富含脂质的炎性斑块。 血管壁内的病变。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，能够可靠地检测到脆弱的斑块并识别 高危患者一直是一个挑战。此外，没有显像剂来检测被侵蚀的斑块，更少- 已知的亚型占临床事件的三分之一。趋化因子和趋化因子受体发挥重要作用 通过引导白细胞运输在动脉粥样硬化从发病到临床事件中的作用。我们已经开发出 趋化因子受体靶向正电子发射断层扫描(PET)显像剂 检测体内单核细胞转运的特异性，跟踪斑块的进展和消退。为了进一步 探索这些显像剂在翻译方面的潜力，我们想提出一个研究计划，以 开发新型PET示踪剂，具有识别易损斑块、检测斑块侵蚀等方面的潜力 重要的是要跟踪治疗反应，以改善患者的预后。具体地说，我们将首先优化 设计和合成针对斑块相关靶点的PET示踪剂组合，包括CCR2，CCR5， CXCR3、CD44和TLR2通过受控方式提高无线标记和纵向扩展能力 放射化学和生物共轭化学，以及通过改变电荷的结合亲和力，表面化学和 聚合物涂层材料。其次，我们将在体内进行生物分布研究和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、敏感性和跟踪体内免疫细胞能力的模型 与靶基因表达及斑块特征的相关性。第三，我们将评估 开发成像探针以确定改善结果和与体外结合的治疗反应 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 向FDA申请，并在授权期结束时准备好两个PET示踪剂用于人体试验。这个 这一研究计划的建立不仅将促进靶向PET示踪剂的发展 动脉粥样硬化转译成像，而且在NHLBI任务范围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.