PET Imaging of Pulmonary Fibrosis

描述(由申请人提供)：这项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，用于直接成像肺纤维化。肺纤维化是一种以肺部结疤(纤维化)为特征的疾病。当肺组织变得伤痕累累时，它会干扰人的呼吸能力。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)， 也就是说，没有已知的原因。据估计，美国有9万人受到IPF的影响，全球有500万患者受到影响。没有有效的治疗方法，许多患有这种疾病的人在确诊后只活了大约三到五年。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是一个疾病领域，将从分子成像方法中受益匪浅。IPF患者是在疾病的晚期被发现的，那里的预后很差。一种可以识别早期纤维化的敏感测试在指导干预改变这种毁灭性疾病的进程方面可能有很大的用处。新治疗方法的开发也将受益于一种非侵入性的、敏感的纤维化测量方法。在功能测试之前观察纤维化消退的能力将是监测新治疗方法有效性的有效手段，也可能是在开始大规模、昂贵的临床试验之前在较少数量的受试者中测试有效性的手段。 这项提议是对RFA-HL-12-036，“肺的分子成像”的回应。特别是，它满足了对“纤维化活动和疤痕形成的探头”的具体需求。为了满足RFA的翻译要求，即“探针可用于人体受试者”，我们建议开发一种新型的PET探针。研究新药(IND)应用的监管路径是明确的，PET探针可以利用探索性IND机制，从而在人类受试者中快速证明概念。 我们的方法是采用一种已知的对I型胶原具有亲和力和特异性的多肽。I型胶原的过度产生是纤维化的一个标志。我们以前曾使用这种与Gd结合的多肽进行心脏和肝脏纤维化的磁共振成像。在这里，我们将修改多肽，加入一个正电子发射体，以利用PET的高敏感性，以量化肺纤维化。初步数据表明，这种方法在图像纤维化方面是可行的。这项提议旨在优化一种胶原蛋白特异的PET探针，以供最终的人类使用。在目标1中，我们用氟-18正电子发射体构建化合物文库和标记探针，以确定具有最佳胶原亲和力、特异性和代谢稳定性的探针。在目标2中，我们检验了胶原蛋白特异性探针在识别和量化小鼠模型中纤维化的有效性。在目标3中，我们展示了一种优化的胶原特异性PET探针在猪肺纤维化模型中的应用。这项研究的成果将是一种新型的纤维化成像探针，具有被证明的有效性、药代动力学特征和临床前剂量学数据，使其能够快速转换为人类使用。

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.