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。肺移植是一种成熟的外科干预，用于晚期肺结核。 肺内科疾病。尽管外科手术的改进， 在免疫抑制治疗范例中，中位存活率持续为6年。 文献先例表明，慢性肺移植物功能障碍（CLAD）是最重要的障碍 肺移植的长期存活率。然而，使用LAD的预测和早期诊断 目前的技术仍然存在问题，由于较低的灵敏度（HRCT）和特异性 （循环生物标志物）。目前，检测急性排斥反应的参考标准是 经支气管活检（TBB）的组织病理学分级，然而，它是一种侵入性技术， 几个局限性（出血、不一致的结局、与重复治疗相关的固有风险） 包括在疾病晚期进行检测。因此，能够 提供移植后慢性排斥反应的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 目的：研制一种新的PET示踪剂（68 Ga-Galalumox）， 急性肺损伤的评估，也表明有希望的更高的吸收肺泡 巨噬细胞的小鼠离体肺移植模型的CLAD，和人肺受体与 CLAD诊断与无CLAD受试者相比。最后，初步68 Ga-Galalumox临床前 在我们的小鼠CLAD模型中的PET成像显示（在尾静脉注射后30分钟）2倍高的 与未患病的患者相比，左移植肺中存在CLAD的早期体征 （未移植）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的活化， 单细胞Galalumox摄取通过检测其天然荧光。有了这些支持， 信息，我们的临床前翻译RO 1的目的是：目的1：目的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， Galallox准备IND申请;目标2：使用68 Ga-Galallox进行首次人体研究： 评价静息时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）;和目的3：评价68 Ga-Galaluminox和18F-FDG用于 肺移植小鼠模型中CLAD发病机制的检测;目的3.1：确定是否 68 Ga-Galaluminox可以检测早期和晚期CLAD发病机制;目的3.2：确定68 Ga-Galaluminox是否可以检测早期和晚期CLAD发病机制。 Galalumox可用于评估对CLAD治疗的反应; 表征68 Ga-Galumorox通过细胞蓄积、亚细胞定位的机制 分馏研究、药代动力学和存在或不存在LPS诱导的炎症 mitoTempo（MTT）和右雷佐生（DEX）在啮齿动物中的作用，以评估其作为非侵入性 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性报告探针作为诊断工具， 具有CLAD风险因素的患者分层; B）潜在的新介入机会; c） 使得能够对疾病病理学进行纵向研究;以及d）监测药物的治疗功效。 综合因素可以显著提高CLAD患者的管理水平， 在早期阶段。