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

用于炎症中凯莫瑞受体靶向成像的新型蛋白酶激活示踪剂

基本信息

批准号：
9892465
负责人：
Sina Tavakoli
金额：
$ 19.56万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9892465
关键词：
Address Affinity Amino Acids Animal Model Binding Biological Blood Circulation C-terminal CMKLR1 gene Cardiovascular Diseases Cathepsins Cells Chelating Agents Chemotactic Factors Chemotaxis Induction Chronic Cleaved cell Colitis Demyelinating Diseases Dendritic Cells Development Disease Disease Progression Early Diagnosis Early identification Elastases Freund&apos s Adjuvant G-Protein-Coupled Receptors GTP-Binding Protein alpha Subunits, Gs Goals Histologic Human Immune Immunomodulators Inflammation Inflammatory Kinetics Label Lead Ligands Mediating Modification Monitor Mus N-terminal Natural Killer Cells Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patient Monitoring Penetrance Penetration Peptide Hydrolases Peptides Plasma Plasmin Play Pneumonia Polyvinyl Alcohol Porifera Process Proteins Pulmonary Inflammation Radiolabeled Regulation Reporting Risk stratification Role Serum Signal Transduction Site Specificity Sterility Structure Time Tissues Tracer Translations Validation Vertebrates base body system chemokine chemokine receptor clinical practice design disorder risk extracellular fluorodeoxyglucose imaging approach imaging probe immunoregulation implantation improved in vivo in vivo imaging in vivo monitoring independency indexing innovation macrophage molecular imaging monocyte mouse model nanomolar novel patient stratification precision medicine prototype radiotracer receptor recruit response subcutaneous targeted imaging uptake

项目摘要

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.

新型蛋白酶 - 可激活化学蛋白衍生的示踪剂，用于分子成像的炎抽象的炎症的分子成像可以尽早鉴定病原多种疾病的过程，可能会导致患者的风险分层改善监测疾病的进展或对治疗的反应。因此，它代表了一个主要驱动程序精确医学，特别是随着新颖的发展和应用免疫调节治疗学。但是，当前分子成像示踪剂的局限性（例如，特异性低和次优的动力学）是成功目标的主要挑战特定炎症过程的成像。我们合成了99mtc标记的高级原型亲和肽，源自相对较近鉴定的趋化因子的羧基末端，即，chemerin，由表达化学蛋白受体1的巨噬细胞内在化（也已知如趋化因子样受体1（CMKLR1）。该提议的目的是进一步发展通过合成和优化新型可活化单体和可裂解的方法炎症中化学蛋白-CMKLR1轴体内成像的多聚体示踪剂。我们的中心假设是，可激活的化学蛋白衍生成像探针的独特设计允许通过利用：a）蛋白酶 - 介导的活化机制，b）免疫细胞的CMKLR1表达相对限制， c）高亲和力和随后的受体介导的C末端肽的内在化，以及 d）增强多聚体肽的动力学。我们提出了两个具体目标：具体目标 1：开发和优化可蛋白酶的可分离单体和可裂解的多聚体化学蛋白派生的放射性示例。特定目的2：使用选定的体内成像验证体内成像的准确性在无菌炎症的鼠模型中优化了示踪剂。我们预测高度的物种 - 示踪剂的独立性，这些独立性来自高度保守的羧基末端化学。因此，这种方法可以应用于多种动物模型，最终在人类。我们的最终目标是开发一种创新的方法来针对性成像重要的免疫调节途径，即Chemerin-CMKLR1轴，可以提供一个场地用于各种炎症性疾病的精确药物。