Chemical Probes for In Vivo Fibrin Imaging

用于体内纤维蛋白成像的化学探针

• 批准号: 8943076
• 负责人: Zhaoda Zhang
• 金额: $ 46.7万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-08 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8943076
• 关键词: Address; Affect; Affinity; Animal Model; Binding; Biological Assay; Biology; Blood coagulation; Carotid Artery Thrombosis; Chemicals; Clinical; Clinical Trials; Complex; Crystallization; Data; Deep Vein Thrombosis; Deposition; Development; Disease; Environment; Extracellular Matrix; Fibrin; Fibrin split products; Fibrinogen; Fluorine; Gadolinium; Goals; Hemostatic function; Human; Image; Ischemic Stroke; Isotopes; Kidney; Lead; Ligand Binding; Liver; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Modeling; Modification; Molecular Bank; Mus; Myocardial Infarction; Neoplasm Metastasis; Optics; Output; Pathology; Patients; Peptide Metabolism; Peptides; Pharmaceutical Chemistry; Positron; Positron-Emission Tomography; Pre-Clinical Model; Production; Prosthesis; Proteins; Publications; Pulmonary Embolism; Radioactive; Rattus; Reporter; Research; Serum Proteins; Solid Neoplasm; Specificity; Structure; Structure-Activity Relationship; Thrombosis; Thrombus; Tumor Biology; Tumor Cell Invasion; Work; Xenograft Model; analog; base; chemical synthesis; cost; database structure; design; extracellular; gadolinium oxide; high throughput screening; imaging probe; improved; in vivo; in vivo imaging; insight; metastatic process; molecular imaging; optical imaging; pharmacophore; programs; public health relevance; radiochemical; scale up; single photon emission computed tomography; small molecule; small molecule libraries; success; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop a sensitive chemical probe for in vivo molecular imaging of fibrin. Fibrin is a major component of thrombus (blood clot), and thrombus is implicated in a range of pathologies, e.g. ischemic stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. Beyond hemostasis, it is known that most solid tumors are characterized by the presence of a fibrin-rich provisional matrix. Tumor invasion/metastasis absolutely requires modification of extracellular matrix components to form a suitable tumor microenvironment. Dvorak's landmark 1986 NEJM publication and subsequent research have carefully delineated the importance of the extracellular environment, and in particular, fibrin deposition, in the metastatic process. Imaging of fibrin using a fibrin-specific molecule conjugated to an optical, magnetic resonance (MR), or radioactive reporter could provide insights into the biology of all these diseases. Fibrin probes could be used to identify thrombi or tumor metastases and to guide patient management. We used a high throughput screening (HTS) assay which was implemented through the Molecular Libraries Probe Production Centers Network (MLPCN) program and resulted in the identification a lead small molecule FB-1. Initial structure-activity studies identified a compound FB-30 with 6-fold higher affinity than FB-1. Here we propose to optimize the affinity of FB-30, to derivatize ths optimized lead with an imaging reporter, and to demonstrate the utility of these chemical probes by imaging fibrin in three animal models. We will use a combination of classical medicinal chemistry and structure-based design by crystallizing the soluble fibrin degradation product DD(E). The structure-activity and structure-based data will also inform on where to conjugate an imaging reporter without adversely affecting fibrin affinity. We will incorporate a positron emittig isotope (likely F-18) into our optimized lead to create a PET imaging probe. We will also conjugate one or more gadolinium chelates into the optimized lead in order to create an MR probe. To demonstrate utility we will use imaging to evaluate these probes in animal models of thrombosis (high fibrin content) and cancer. The output of this work will be chemical probes for selective in vivo imaging of fibrin.

 描述（由申请人提供）：本提案的目标是开发一种用于纤维蛋白体内分子成像的敏感化学探针。血栓是血栓（血凝块）的主要成分，并且血栓涉及一系列病理，例如缺血性中风、心肌梗死、肺栓塞和深静脉血栓形成。除了止血之外，已知大多数实体瘤的特征在于存在富含纤维蛋白的临时基质。肿瘤侵袭/转移绝对需要细胞外基质成分的修饰以形成合适的肿瘤微环境。Dvorak在1986年的NEJM出版物和随后的研究中仔细描述了细胞外环境，特别是纤维蛋白沉积在转移过程中的重要性。成像 使用纤维蛋白特异性分子与光学、磁共振（MR）或放射性报告分子结合，对纤维蛋白的研究可以提供对所有这些疾病的生物学的见解。可使用纤维探针来识别血栓或肿瘤转移，并指导患者管理。我们使用了高通量筛选（HTS）试验，该试验通过分子库探针生产中心网络（MLPCN）计划实施，并鉴定了一种先导小分子FB-1。最初的结构-活性研究鉴定了具有比FB-1高6倍的亲和力的化合物FB-30。在这里，我们建议优化FB-30的亲和力，衍生化优化的铅与成像报告，并证明这些化学探针的效用，通过成像纤维蛋白在三种动物模型。我们将通过结晶可溶性纤维蛋白降解产物DD（E），结合经典药物化学和基于结构的设计。结构-活性和基于结构的数据还将告知在何处缀合成像报告物而不会不利地影响纤维蛋白亲和力。我们将在优化的电极导线中加入正电子发射同位素（可能是F-18），以创建PET成像探头。我们还将一种或多种钆螯合物结合到优化的电极导线中，以创建MR探头。为了证明实用性，我们将使用成像来评估这些探针在血栓形成（高纤维蛋白含量）和癌症的动物模型。这项工作的输出将是纤维蛋白的选择性体内成像的化学探针。