Optimization of PET probe for imaging lung fibrogenesis

肺纤维化成像 PET 探针的优化

• 批准号: 10054488
• 负责人: Peter D Caravan
• 金额: $ 58.8万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10054488
• 关键词: Address; Affinity; Aldehydes; Animal Model; Area; Binding; Biochemical; Biological Assay; Biopsy; Bleomycin; Blood Vessels; Blood specimen; Cicatrix; Clinical; Clinical Trials; Collagen; Detection; Development; Diagnosis; Disease; Disease Progression; Dose; Drug Kinetics; Early Diagnosis; Early treatment; Fibrosis; Funding; Goals; Hand; Heart; Hepatobiliary; High Resolution Computed Tomography; Human; Image; Imaging Device; In Vitro; Individual; Indoles; Inflammatory; LOX gene; Label; Lead; Libraries; Liver; Liver Fibrosis; Lung; Magnetic Resonance; Measures; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Probes; Monitor; Mus; Natural History; Oxides; Pathogenicity; Patient Care; Patients; Pharmacotherapy; Phase; Positron-Emission Tomography; Property; Pulmonary Fibrosis; Pulmonary function tests; Rattus; Reporting; Respiratory physiology; Selection for Treatments; Serum; Signal Transduction; Specificity; Structure of parenchyma of lung; Time; Tissues; Tracer; Translating; Work; anatomic imaging; clinical development; clinical translation; design; drug development; fibrogenesis; hydrophilicity; idiopathic pulmonary fibrosis; imaging probe; improved; in vivo; indium-bleomycin; inhibitor/antagonist; injured; lead optimization; lead series; lung imaging; lung injury; lung lobe; molecular imaging; mouse model; nonhuman primate; optimal treatments; quantitative imaging; standard of care; treatment response; uptake

Project Summary/Abstract The goal of this project is to optimize a positron emission tomography (PET) probe to quantify fibrogenesis (active disease) in the lung to ultimately provide an early diagnosis of idiopathic pulmonary fibrosis (IPF), to predict disease progression, and to provide an early indication of whether anti-fibrotic therapy is likely to be effective. IPF is a progressive and ultimately fatal disease with a median survival of less than 4 years from the time of diagnosis. The treatment options remain limited due to highly variable clinical course and poorly understood pathogenic mechanisms. Current strategies to diagnose and monitor IPF include lung biopsy, pulmonary function tests that measure global lung function, and anatomic imaging tools such as high-resolution computed tomography (HRCT). Yet these methods are limited in their ability to detect disease early, determine disease activity at any one measure, or monitor the therapeutic response. Our group recently demonstrated that oxidized collagen is a marker of active disease in pulmonary fibrosis. In animal models, using molecular probes that target the allysine residue on oxidized collagen, we showed that a molecular probe targeted to allysine could detect fibrogenesis, monitor treatment response and could distinguish active fibrogenesis from stable scar in models of lung fibrosis. We further showed that by modifying the affinity and reactivity (on-rate), that probe uptake in areas of active disease could be increased in a rational manner. In this Catalyze: Preliminary Product/Lead Series Identification proposal, we aim to optimize our lead PET probe with respect to its uptake in areas of disease and its elimination from non-diseased lung and surrounding tissues, thus providing a very high target to background ratio and enabling accurate quantification of lung fibrogenesis. With the optimized probe in hand, we will then demonstrate its efficacy in different animal models of pulmonary fibrosis, demonstrate its specificity to quantify active disease, and show that it can monitor treatment response. At the end of this two year project we will have an optimized and validated PET probe for imaging lung fibrogenesis and be poised to translate this probe to human clinical trials.

项目摘要/摘要 这个项目的目标是优化一种正电子发射断层扫描(PET)探头来量化纤维化形成。 (活动性疾病)最终提供特发性肺纤维化(IPF)的早期诊断， 预测疾病的进展，并提供早期迹象表明抗纤维化治疗是否可能 有效。IPF是一种进行性并最终致命的疾病，中位生存期不到4年 诊断时间。由于高度多变的临床病程和糟糕的治疗方案，治疗选择仍然有限 了解致病机制。目前诊断和监测IPF的策略包括肺活检， 测量全球肺功能的肺功能测试，以及高分辨率等解剖成像工具 计算机断层扫描(HRCT)。然而，这些方法在早期发现疾病、确定 任何一项指标的疾病活动性，或监测治疗反应。我们小组最近证明了 氧化胶原蛋白是肺纤维化活动性疾病的标志。在动物模型中，使用分子探针 针对氧化后的胶原上的大蒜素残基，我们发现针对大蒜素的分子探针可以 检测纤维化形成，监测治疗反应，并可区分活动期纤维化和稳定期瘢痕 肺纤维化模型。我们进一步证明，通过改变亲和力和反应性(ON-Rate)，该探针摄取 可以以合理的方式增加活动性疾病地区的医疗费用。 在这个催化剂：初步的产品/铅系列鉴定建议中，我们的目标是优化我们的铅PET 关于其在病区的摄取和从非病变肺及周围清除的探讨 组织，从而提供非常高的目标与背景的比率，并使得能够准确地量化肺 纤维化。有了优化的探针，我们将在不同的动物模型中展示其有效性 肺纤维化，证明其特异性，以量化活动性疾病，并表明它可以监测 治疗反应。在这个为期两年的项目结束时，我们将有一个优化和验证的PET探测器 成像肺纤维化，并准备将这一探测器转化为人类临床试验。