PET Tracer for Imaging of Lung Inflammation

用于肺部炎症成像的 PET 示踪剂

• 批准号: 10682270
• 负责人: Andrew Eric Gelman
• 金额: $ 73.05万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682270
• 关键词: A549; Acute; Acute Lung Injury; Aging; Air; Allografting; Alveolar Macrophages; Alzheimer' s Disease; Apoptosis; Asthma; Atherosclerosis; Biochemical; Biodistribution; Biopsy; Blood Vessels; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; Cardiovascular Diseases; Cell Culture Techniques; Cell Fractionation; Cell Line; Cells; Characteristics; Chronic; Chronic Disease; Chronic lung disease; DNA; Data; Detection; Development; Dexrazoxane; Diabetes Mellitus; Diagnosis; Diagnostic; Diameter; Discipline of Nuclear Medicine; Disease; Dose; Drug Kinetics; Early Diagnosis; Epithelial Cells; Exhalation; Female; Flow Cytometry; Fluorescence; Fluorescent Dyes; Free Radicals; Functional disorder; Generations; Genetic Transcription; Graft Rejection; Hemorrhage; Histologic; Histopathologic Grade; Homeostasis; Human; Hydrogen Peroxide; Image; Immunosuppression; Infiltration; Inflammation; Injections; Intervention; Lead; Left; Life; Lipids; Literature; Location; Longitudinal Studies; Lung; Lung Transplantation; Lung diseases; Macrophage Activation; Measures; Mediating; Membrane; Metabolism; Mitochondria; Modeling; Mole the mammal; Molecular; Monitor; Mus; Names; Non-Invasive Detection; Operative Surgical Procedures; Organ Transplantation; Outcome; Oxidation-Reduction; Oxidative Stress; Oxygen; PET/CT scan; Pathogenesis; Pathology; Patients; Performance; Phase; Physiological; Pilot Projects; Play; Positron-Emission Tomography; Pre-Clinical Model; Procedures; Production; Proteins; Psoriasis; Pulmonary Fibrosis; Pulmonary Inflammation; Pulmonology; Radiometry; Reactive Oxygen Species; Reference Standards; Regimen; Reporter; Reporting; Resources; Rest; Rheumatoid Arthritis; Risk; Risk Factors; Rodent; Role; Running; Safety; Saline; Signal Transduction; Skeletal Muscle; Solid; Specificity; Specimen; Structure of parenchyma of lung; Structure-Activity Relationship; Superoxides; Survival Rate; System; Tail; Techniques; Therapeutic; Tissues; Toxicology; Tracer; Translations; Transplantation; Treatment Efficacy; Validation; Veins; alveolar epithelium; circulating biomarkers; cohort; detection method; diagnostic tool; dosimetry; drug efficacy; fibrotic lung disease; first-in-human; fluorescence imaging; fluorodeoxyglucose; image guided; imaging agent; imaging probe; improved; infection risk; lung allograft; lung imaging; lung injury; male; mitochondrial dysfunction; molecular imaging; mouse model; muscle physiology; nano; oxidized lipid; pathogen; patient stratification; pre-clinical; preclinical development; radiotracer; response; tool; transplant model; uptake

Abstract. Lung transplantation is a well-established surgical intervention in advanced stages of the disease in pulmonary medicine. Despite improvements in surgical procedures and immunosuppressive therapeutic paradigms, the median survival rate continues to be 6 years. Literature precedents show that chronic lung allograft dysfunction (CLAD) is the most significant barrier to long-term survival of lung transplantation. However, prediction and early diagnosis of CLAD using current techniques continues to be problematic due to lower sensitivity (HRCT) and specificity (circulating biomarkers). Currently, the reference standard to detect acute rejection is a histopathological grading of transbronchial biopsies (TBBs), however, it is an invasive technique with several limitations (bleeding, inconsistent outcomes, inherent risks associated with repetitive procedures) including detection at advanced stages of the disease. Therefore, agents capable of offering non-invasive assessment of chronic rejection after transplantation are a highly desirable diagnostic nuclear medicine resource, yet continues to be an unmet need. To accomplish this objective, we have developed a new PET tracer (named as 68Ga-Galuminox), which offers noninvasive assessment of acute lung injury, and also demonstrates promising higher uptake in alveolar macrophages of mouse ex vivo lung transplant model of CLAD, and human lung recipients with a CLAD diagnosis compared to CLAD free subjects. Finally, preliminary 68Ga-Galuminox preclinical PET imaging in our mouse CLAD model has revealed (at 30 min post tail-vein injection) 2-fold higher retention in the left transplanted lung with early signs of CLAD when compared to the non-diseased (untransplanted) right lung. Notably, these observations are also consistent with the observed activation of macrophages and PMNs in CLAD lungs as measured by flow cytometry that identifies single cell Galuminox uptake by detecting its native fluorescence. Armed with this supporting information, aims of our preclinical translational RO1 are: Aim 1: Aim 1: Perform radiation dosimetry to determine human effective dose equivalent (HED), toxicology studies, and GMP validation runs for Galuminox to prepare for an IND filing; Aim 2: Perform first-in-human studies using 68Ga-Galuminox: evaluate dosimetry, biodistribution, safety, and imaging characteristics following a single injection at rest (n=8, 4 males; 4 females); and Aim 3: To evaluate performance of 68Ga-Galuminox and 18F-FDG for detection of CLAD pathogenesis in a mouse model of lung transplantation; Aim 3.1: To determine if 68Ga-Galuminox can detect early and late CLAD pathogenesis; Aim 3.2: To determine if 68Ga- Galuminox can be used to evaluate responses to CLAD treatment; and Aim 3.3: Biochemically characterize mechanism(s) of location of the 68Ga-Galuminox through cell accumulation, sub-cellular fractionation studies, pharmacokinetics, and LPS-induced inflammation either in presence or absence of mitoTempo (MTT) and Dexrazoxane (DEX) in rodents to assess its ability to serve as noninvasive molecular imaging agent for monitoring lung injury. Successful accomplishment of proposed aims could enable: a) deployment of a noninvasive redox-sensitive reporter probe as a diagnostic tool for stratification of patients with a risk factor for CLAD; b) potentially new interventional opportunities; c) enabling longitudinal studies of disease pathology; and d) monitoring therapeutic efficacy of drugs. Combined factors could significantly advance management of CLAD patients with potential detection of CLAD at earliest stages.

抽象的。肺移植是一种行之有效的晚期手术干预方法 肺部医学疾病。尽管外科手术方法有所改进， 免疫抑制治疗范式的中位生存率仍然为 6 年。 文献先例表明，慢性同种异体肺移植功能障碍（CLAD）是最重要的障碍 肺移植后才能长期存活。然而，使用 CLAD 进行预测和早期诊断 由于灵敏度 (HRCT) 和特异性较低，当前技术仍然存在问题 （循环生物标志物）。目前，检测急性排斥反应的参考标准是 然而，经支气管活检 (TBB) 的组织病理学分级是一种侵入性技术 一些限制（出血、结果不一致、与重复性相关的固有风险） 程序），包括疾病晚期的检测。因此，代理人有能力 对移植后慢性排斥反应进行非侵入性评估是非常可取的 诊断核医学资源，但仍然是一个未满足的需求。为了实现这一点 为了实现这一目标，我们开发了一种新型 PET 示踪剂（命名为 68Ga-Galuminox），它提供了无创性 急性肺损伤的评估，并且还表明有希望在肺泡中获得更高的摄取 CLAD小鼠离体肺移植模型和人肺受体的巨噬细胞 CLAD 诊断与无 CLAD 受试者的比较。最后，初步68Ga-Galuminox临床前 我们的小鼠 CLAD 模型中的 PET 成像显示（尾静脉注射后 30 分钟）高出 2 倍 与未患病的肺相比，左移植肺中保留有 CLAD 的早期症状 （未移植的）右肺。值得注意的是，这些观察结果也与观察到的一致 通过流式细胞术测量 CLAD 肺中巨噬细胞和 PMN 的激活，识别 通过检测其天然荧光来单细胞摄取 Galluminox。有了这个支撑 信息，我们的临床前转化 RO1 的目标是： 目标 1： 目标 1： 进行辐射剂量测定 确定人体有效剂量当量 (HED)、毒理学研究和 GMP 验证运行 Galluminox 准备 IND 申请；目标 2：使用 68Ga-Galuminox 进行首次人体研究： 评估静息单次注射后的剂量测定、生物分布、安全性和成像特征 (n=8，4名男性；4名女性)；目标 3：评估 68Ga-Galuminox 和 18F-FDG 的性能 小鼠肺移植模型中CLAD发病机制的检测；目标 3.1：确定是否 68Ga-Galuminox可检测早期和晚期CLAD发病机制；目标 3.2：确定 68Ga- Galluminox 可用于评估 CLAD 治疗的反应；目标 3.3：生化 通过细胞积累、亚细胞表征 68Ga-Galuminox 的定位机制 存在或不存在时的分级研究、药代动力学和 LPS 诱导的炎症 MitoTempo (MTT) 和 Dexrazoxane (DEX) 在啮齿类动物中的应用，以评估其作为非侵入性药物的能力 用于监测肺损伤的分子成像剂。成功实现拟议目标 可以实现：a）部署非侵入性氧化还原敏感报告探针作为诊断工具 对具有 CLAD 危险因素的患者进行分层； b) 潜在的新干预机会； c) 实现疾病病理学的纵向研究； d) 监测药物的治疗效果。 综合因素可以通过潜在的检测显着推进 CLAD 患者的管理 CLAD 的最早阶段。