PET Tracer for Imaging of Lung Inflammation

抽象的。肺移植是一种成熟的外科治疗晚期肺癌的方法。 肺部医学中的疾病。尽管外科手术程序有所改进， 免疫抑制治疗方案，中位生存期持续6年。 文献先例表明，慢性肺移植功能障碍(Clad)是最重要的障碍。 对肺移植的长期存活至关重要。然而，衣原体感染的预测和早期诊断 由于敏感性(HRCT)和特异性较低，目前的技术仍然存在问题 (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，经支气管镜活检的组织病理学分级是一种侵入性技术。 几个限制(出血、结果不一致、与重复相关的固有风险 程序)，包括在疾病晚期进行检测。因此，有能力 提供移植后慢性排斥反应的无创性评估是非常可取的 诊断核医学资源，但仍是一个未得到满足的需求。要做到这一点 目的：我们研制了一种新的PET示踪剂，命名为68Ga-Galnuox，它提供了一种无创的 评估急性肺损伤，也显示肺泡有较高的摄取 小鼠体外肺移植模型的巨噬细胞及人肺移植受者 穿着衣服的诊断与不穿衣服的受试者比较。最后，68Ga-GalLumox初步临床前 在我们的小鼠包衣模型中，PET成像显示(尾静脉注射后30分钟)高出2倍 与非病变患者相比，左侧移植肺中有包膜早期征象的肺内滞留 (未移植的)右肺。值得注意的是，这些观察结果也与观察到的 用流式细胞仪检测包膜肺中巨噬细胞和中性粒细胞的激活 通过检测其天然荧光来摄取单细胞Galnuox。有了这样的支持 信息，我们临床前转译RO1的目标是：目标1：目标1：执行辐射剂量测量 为了确定人体有效剂量当量(HED)，毒理学研究和GMP验证运行 Galnuox为IND申请做准备；目标2：使用68Ga-Galnuox进行首例人体研究： 评估静息单次注射后的剂量学、生物分布、安全性和成像特征 (n=8，男4，女4)；目标3：评价~(68)Ga-Galnuox和~(18)F-FDG在 在小鼠肺移植模型中检测CLAD发病机制；目的3.1：确定 68Ga-Galnuox可检测早期和晚期包膜发病；目的3.2：确定68Ga-Galnuox Galnuox可用于评估包衣治疗的反应；目标3.3：生化 从细胞积聚、亚细胞表征68Ga-GalLumox定位机制(S) 存在或不存在时的分级研究、药代动力学和脂多糖诱导的炎症 四甲基偶氮唑蓝(四甲基偶氮唑蓝)和右旋糖苷(DEX)在啮齿动物体内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显像剂。成功实现拟议目标 可实现：a)部署非侵入性氧化还原敏感的报告探针，作为诊断工具 对有危险因素的患者进行分层；b)潜在的新的介入机会；c) 使疾病病理学的纵向研究成为可能；以及d)监测药物的治疗效果。 联合因素可显著促进潜在检测到的衣着患者的管理 在最早的阶段就被穿上了。

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.