Novel Protease-Activatable Tracers for Targeted Imaging of Chemerin Receptor in Inflammation

一种新型的可激活酶促细胞色素的分子成像示踪剂 炎症 摘要 炎症的分子成像可以早期识别致病因素 在广泛的疾病中的过程，并可能导致改善患者和 监测疾病进展或对治疗的反应。因此，它代表着一个主要的驱动力 精准医学的发展，特别是随着新药的发展和应用的日益广泛 免疫调节疗法。然而，目前分子成像示踪剂的局限性 (例如，低特异性和次优动力学)一直是成功靶向的主要挑战 特定炎症过程的成像。我们已经合成了99mTc标记的高能核素的原型。 亲和肽，来源于最近发现的一种趋化因子的羧基末端， 即趋化蛋白，它由表达趋化蛋白受体1的巨噬细胞内化(也称为 即趋化素样受体1(CMKLR1)。这项提议的目标是进一步推进这一目标 新型可活化单体和可裂解单体的合成与优化 多聚体示踪剂用于炎症中趋化蛋白-CMKLR1轴的体内成像。我们的中央 假设是可激活的趋化蛋白衍生的成像探针的独特设计允许 为了准确地在体内监测炎症，通过利用以下优势：a)蛋白酶- B)免疫细胞相对限制CMKLR1的表达， C)高亲和力和随后受体介导的C端肽的内化，以及 D)增强了多聚肽的动力学。我们提出了两个具体目标：具体目标 1：开发和优化蛋白酶激活的单体和可切割的多聚体趋化蛋白- 衍生的放射性示踪剂。特定目的2：验证选择的活体成像的准确性 无菌炎症小鼠模型中的优化示踪剂。我们预测会有高度的物种- 我们的示踪剂的独立性，这些示踪剂来自高度保守的 趋化因子。因此，这种方法可以应用于各种动物模型，并最终应用于 人类。我们的最终目标是开发一种创新的方法，用于靶向成像 重要的免疫调节途径，即趋化蛋白-CMKLR1轴，可能为 用于各种炎症性疾病的精准医学。

Novel Protease-Activatable Chemerin-Derived Tracers for Molecular Imaging of Inflammation ABSTRACT Molecular imaging of inflammation allows for early identification of the pathogenic processes in a wide range of diseases and may lead to improved risk stratification of patients and monitoring the progression of disease or response to therapy. Thus, it represents a major driver of Precision Medicine, particularly with the growing development and applications of novel immunomodulatory therapeutics. However, limitations of the current molecular imaging tracers (e.g., low specificity and suboptimal kinetics) have been major challenges to successful targeted imaging of specific inflammatory processes. We have synthesized a prototype 99mTc-labeled high- affinity peptide, derived from the carboxy-terminus of a relatively recently identified chemokine, i.e., chemerin, which is internalized by macrophages expressing chemerin receptor 1 (also known as chemokine-like receptor 1 (CMKLR1). The goal of this proposal is to further advance this approach by the synthesis and optimization of novel activatable monomeric and cleavable multimeric tracers for in vivo imaging of chemerin-CMKLR1 axis in inflammation. Our central hypothesis is that the unique design of the activatable chemerin-derived imaging probes allows for accurate in vivo monitoring of inflammation, through taking advantage of: A) protease- mediated activatable mechanism, B) relatively restricted expression of CMKLR1 by immune cells, C) high affinity and subsequent receptor-mediated internalization of the C-terminal peptides, and D) enhanced kinetics of the multimeric peptides. We propose two Specific Aims: SPECIFIC AIM 1: To develop and optimize protease-activatable monomeric and cleavable multimeric chemerin- derived radiotracers. SPECIFIC AIM 2: To validate the accuracy of in vivo imaging using selected optimized tracers in murine models of sterile inflammation. We predict a high degree of species- independency of our tracers, which are derived from the highly conserved carboxy-terminus of chemerin. Thus, this approach may be applied in a variety of animal models and ultimately in humans. Our ultimate goal is to develop an innovative approach for targeted imaging of an important immunoregulatory pathway, i.e., chemerin-CMKLR1 axis, which may provide a venue for precision medicine in a variety of inflammatory diseases.