Noninvasive Nephritis Imaging

项目概要/摘要。 炎症在许多肾脏疾病状态中起着关键的致病作用。因此， 诊断、绘制和纵向监测肾脏炎症可以大大提高我们识别和 治疗患有与药物毒性、局部缺血、感染、自身免疫性疾病相关的肾损伤的患者，以及 同种异体移植物功能障碍不幸的是，肾脏炎症的明确诊断需要活检， 侵入性的、昂贵的、造成大量出血的风险，并且仅对肾脏的一小部分进行采样。重复活检 对于纵向患者监测是不切实际的。此外，许多需要活检的患者 禁忌症包括肥胖、抗凝、重度高血压或单肾。 在许多疾病中，存在对非侵入性地检测、映射、量化和监测炎症的迫切未满足的需求。 肾脏疾病状态。目前可用的成像技术可能会识别肾脏 炎症，如[18F]氟-2-脱氧葡萄糖（FDG）正电子发射断层扫描（PET）具有重要 局限性，缺乏足够的空间分辨率进行疾病绘图，使患者暴露于电离辐射，以及 FDG既经肾脏排泄，又在近端小管中部分重吸收，这一事实使FDG的可视化变模糊， 实质炎性浸润。实验性超小顺磁性氧化铁纳米颗粒（USPIONs） 在临床试验中，靶向吞噬细胞的方法已被用于对肾脏炎症进行成像，但这种方法 受缓慢的USPION药代动力学的限制，在注射和成像读出之间需要几天。 一种理想的肾脏炎症分子成像技术应该不会产生背景信号， 肾脏，在炎症存在时产生阳性信号增强，并产生炎症- 在注射后数分钟内进行特定成像读数。我们保证能满足这些技术标准 使用最近发明的新型活性氧（ROS）响应MR成像探针， 我们的实验室升高的细胞外ROS浓度是发炎组织的标志性特征，如粒细胞 先天免疫系统的细胞经历呼吸爆发，导致异常氧化组织 微环境我们的ROS特异性造影剂Fe-PyC 3A是一种低分子量铁复合物， 在ROS存在的情况下，在MR静默和MR可见状态之间瞬时切换。 该R21的目标是通过证明Fe-PyC 3A作为肾脏炎症成像的工具， 在缺血和免疫相关肾脏疾病的小鼠模型中的概念验证， 肾脏MR成像，并证明肾脏成像应用的安全性。该提案写在 对PAR-20-140“肾脏、泌尿系统和血液系统的催化工具和技术开发”的回应 疾病，”并特别强调了“创新的新放射学方法和新的成像探头”的要求。 排斥模型中的肾脏隔室。

Project Summary/Abstract. Inflammation plays a key pathogenic role in numerous kidney disease states. Accordingly, procedures to diagnose, map, and longitudinally monitor kidney inflammation can greatly enhance our ability to identify and treat patients suffering from kidney injury related to drug toxicity, ischemia, infection, autoimmune diseases, and allograft dysfunction. Unfortunately, definitive diagnosis of kidney inflammation requires biopsy, which is invasive, costly, poses substantial bleeding risk, and samples only a small segment of the kidney. Repeat biopsy is impractical for longitudinal patient monitoring. Furthermore, many patients requiring biopsy have contraindications including obesity, anticoagulation, severe hypertension, or single kidney. There is an urgent unmet need to noninvasively detect, map, quantify, and monitor inflammation in numerous kidney disease states. Currently available imaging technologies which could potentially identify kidney inflammation, such as [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) have important limitations, lacking sufficient spatial resolution for disease mapping, exposing patients to ionizing radiation, and the fact that FDG is both renally excreted and partially reabsorbed in proximal tubules blunts visualization of parenchymal inflammatory infiltrates. Experimental ultrasmall paramagnetic iron-oxide nanoparticles (USPIONs) targeted to phagocytic cells have been used to image kidney inflammation in clinical trials, but this approach is limited by slow USPION pharmacokinetics, requiring several days between injection and imaging readout. An ideal technology for molecular imaging of kidney inflammation should generate no background signal in the kidney, generate positive signal enhancement in the presence of inflammation, and yield an inflammation- specific imaging readout within minutes of injection. We posit that we can satisfy these technologic criteria using new class of reactive oxygen species (ROS) responsive MR imaging probe recently invented by our lab. Elevated extracellular ROS concentrations are a hallmark feature of inflamed tissue, as granulocytic cells of the innate immune system undergo respiratory burst resulting in an aberrant oxidizing tissue microenvironment. Our ROS-specific contrast agent, Fe-PyC3A, is a low molecular weight iron complex that instantaneously switches between an MR silent and MR visible states in the presence ROS. The goals of this R21 are to advance Fe-PyC3A as tool for imaging kidney inflammation by demonstrating proof of concept in murine models of ischemia- and immune-related kidney diseases, optimizing the dose for kidney MR imaging, and demonstrating safety for kidney imaging applications. This proposal is written in response to PAR-20-140 “Catalytic Tool and Technology Development in Kidney, Urologic, and Hemotologic Diseases,” and specifically addresses calls for “innovative new radiologic methods and novel imaging probes.” kidney compartments in the rejection model.