PET Imaging of Pulmonary Fibrosis

描述（由申请人提供）：本提案的目标是开发一种I型胶原特异性正电子发射断层扫描（PET）探针，用于肺纤维化的直接成像。肺纤维化是一种以肺部瘢痕形成（纤维化）为特征的疾病。随着肺组织变得疤痕，它干扰了一个人的呼吸能力。在某些情况下，可以找到纤维化的原因，但大多数病例被称为特发性肺纤维化（IPF）， 即原因不明。IPF在美国影响估计90，000人，在全球影响> 500万患者。没有有效的治疗方法，许多患有这种疾病的人在诊断后只能活三到五年。虽然最近的临床试验令人失望，但在临床前阶段有很有希望的治疗方法。IPF是一种将从分子成像方法中获益匪浅的疾病领域。IPF患者在疾病晚期被识别，其中预后差。一个敏感的测试，可以识别早期发病的纤维化可能有很大的效用，在指导干预措施，以改变这种毁灭性的疾病的过程。新的治疗方法的发展也将受益于一种非侵入性的、敏感的纤维化测量方法。在功能测试改变之前看到纤维化消退的能力将是监测新治疗方法的有效手段，并且可以是在开始大型昂贵的临床试验之前在较少数量的受试者中测试疗效的手段。 该提案是对RFA-HL-12-036“肺部分子成像”的回应。特别地，它响应了对“纤维化活性和瘢痕形成的探针”的特定需求。为了解决RFA的翻译要求，即“探针可用于人类受试者”，我们提出了一种新型PET探针的开发。研究性新药（IND）申请的监管路径是明确的，PET探针可以利用探索性IND机制，在人类受试者中快速验证概念。 我们的方法是采取一种已知的肽，具有亲和力和特异性的I型胶原蛋白。I型胶原蛋白的过度产生是纤维化的标志。我们以前使用这种肽共轭钆的MR成像的心脏和肝脏纤维化。在这里，我们将修改肽，以纳入正电子发射器，以利用PET的高灵敏度，以量化肺纤维化。初步数据显示了这种方法对纤维化成像的可行性。该提案旨在优化胶原蛋白特异性PET探针，以最终用于人类。在目标1中，我们建立化合物库，并标记探针与氟-18正电子发射体，以确定最佳的胶原蛋白亲和力，特异性和代谢稳定性的探针。在目标2中，我们检查了胶原特异性探针在识别和定量小鼠模型中纤维化的功效。在目标3中，我们证明了优化的胶原特异性PET探针在肺纤维化猪模型中的实用性。这项研究的成果将是一种新型的纤维化成像探针，具有经证实的疗效、药代动力学表征和临床前剂量测定数据，能够快速转化为人类使用。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a type I collagen-specific positron emission tomography (PET) probe for direct imaging of pulmonary fibrosis. Pulmonary fibrosis is a disease marked by scarring (fibrosis) in the lungs. As the lung tissue becomes scarred, it interferes with a person's ability to breathe. In some cases, the cause of fibrosis can be found, but the majority of cases are termed idiopathic pulmonary fibrosis (IPF), i.e. there is no known cause. IPF affects an estimated 90,000 people in the United States and >5 million patients worldwide. There is no effective treatment and many people with the disease live only about three to five years after diagnosis. While recent clinical trials have been disappointing, there are promising therapies at the preclinical stage. IPF is a disease area that would benefit greatly from a molecular imaging approach. IPF patients are identified at a late stage of disease where prognosis is poor. A sensitive test that can identify early onset of fibrosi may have great utility in guiding interventions to alter the course of this devastating disease. The development of new therapeutic approaches would also benefit from a noninvasive, sensitive measure of fibrosis. The ability to see fibrosis regression prior to changes in functiona tests would be an effective means to monitor the efficacy new therapeutic approaches and could be a means of testing efficacy in smaller numbers of subjects before embarking on large, expensive clinical trials. This proposal is in response to RFA-HL-12-036, "Molecular Imaging of the Lung". In particular it responds to the specific need for "Probes of fibrotic activity and scarring". To address the translational imperative of the RFA that "probes be feasible for use in human subjects", we propose the development of a novel PET probe. The regulatory path to an investigational new drug (IND) application is clear and PET probes can take advantage of the exploratory IND mechanism that results in rapid proof of concept in human subjects. Our approach is to take a known peptide that has affinity and specificity for type I collagen. Overproduction of type I collagen is a hallmark of fibrosis. We have previously used this peptide conjugated to gadolinium for MR imaging of cardiac and liver fibrosis. Here we will modify the peptide to incorporate a positron emitter to take advantage of the high sensitivity of PET in order to quantify fibrosis in the lung. Preliminary data shows the feasibility of this approach to image fibrosis. This proposal aims to optimize a collagen-specific PET probe for ultimate human use. In Aim 1 we build compound libraries and label probes with fluorine-18 positron emitters to identify probes with optimal collagen affinity, specificity, and metabolic stability. In Aim 2, we examine the efficacy of collagen-specific probes in identifying and quantifying fibrosis in mouse models. In Aim 3 we demonstrate the utility of an optimized collagen-specific PET probe in a pig model of pulmonary fibrosis. The output of this research will be a novel fibrosis imaging probe with demonstrated efficacy, pharmacokinetic characterization, and preclinical dosimetry data that enables rapid translation for human use.