Optimization of PET probe for imaging lung fibrogenesis

项目总结/摘要 本项目的目标是优化正电子发射断层扫描（PET）探头，以量化纤维化 肺中的肺纤维化（活动性疾病），以最终提供特发性肺纤维化（IPF）的早期诊断， 预测疾病进展，并提供抗纤维化治疗是否可能 有效IPF是一种进行性和最终致命的疾病，从治疗开始的中位生存期不到4年。 诊断时间。治疗选择仍然有限，由于高度可变的临床过程和不良 了解致病机制。目前诊断和监测IPF的策略包括肺活检， 测量整体肺功能的肺功能测试，以及解剖成像工具，如高分辨率 计算机断层扫描（HRCT）。然而，这些方法在早期发现疾病、确定 疾病活动的任何一个措施，或监测治疗反应。我们的团队最近证明， 氧化胶原是肺纤维化中活动性疾病的标志物。在动物模型中，使用分子探针 针对氧化胶原蛋白上的赖氨酸残基，我们发现针对赖氨酸的分子探针可以 检测纤维化，监测治疗反应，并可以区分活动性纤维化与稳定性瘢痕， 肺纤维化模型。我们进一步表明，通过改变亲和力和反应性（结合率）， 在活动性疾病的地区，可以以合理的方式增加。 在此催化剂：初步产品/铅系列识别提案中，我们的目标是优化我们的铅PET 关于其在疾病区域中的摄取及其从非病变肺和周围环境中的消除的探针 组织，从而提供非常高的目标与背景比，并能够准确定量肺 纤维化有了优化后的探针，我们将在不同的动物模型中证明其有效性 肺纤维化，证明其特异性量化活动性疾病，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探头， 成像肺纤维化，并准备将这种探针转化为人类临床试验。

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.