PET Tracers for Imaging ROS Activity

用于 ROS 活动成像的 PET 示踪剂

• 批准号: 10715916
• 负责人: Vijay Sharma
• 金额: $ 28.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715916
• 关键词: A549; Acute Lung Injury; Acute Respiratory Distress Syndrome; Advisory Committees; Aging; Agreement; Alzheimer' s Disease; Animal Model; Asthma; Atherosclerosis; Bacterial exotoxin; Biochemical; Biological Assay; Blood - brain barrier anatomy; Blood Vessels; Brain; Cardiovascular Diseases; Cardiovascular system; Cells; Cellular Assay; Central Nervous System Diseases; Characteristics; Chemoresistance; Clinic; Compensation; Copper; Cysteine Desulfhydrase; DNA; Data; Detection; Diabetes Mellitus; Diameter; Disease; Drug Kinetics; Epithelium; Fluorescence; Fluorescent Probes; Fluorine; Free Radicals; Functional Imaging; Funding; Future; Gallium; Gastrointestinal tract structure; Generations; Genetic Transcription; Grant; Homeostasis; Human; Hydrogen Peroxide; Hydroxyl Radical; ITGB3 gene; Image; Inflammation; Injury to Kidney; Instruction; Investigation; Ischemia; Lead; Link; Lipids; Location; Lung; Lung Transplantation; Mediating; Meningeal; Metastatic Neoplasm to the Bone; Mitochondria; Modeling; Monitor; Multiple Sclerosis; Nephrotic Syndrome; Neurodegenerative Disorders; Oncology; Optics; Oxidants; Oxidation-Reduction; Oxidative Stress; Oxygen; Parkinson Disease; Pathogenesis; Performance; Pharmacodynamics; Physiological; Positron; Positron-Emission Tomography; Production; Proteins; Psoriasis; Radioisotopes; Reactive Oxygen Species; Recommendation; Reporter; Resources; Rheumatoid Arthritis; Rodent; Rodent Diseases; Rodent Model; Safety; Science; Services; Signal Transduction; Skeletal Muscle; Superoxides; System; Tissues; Tracer; Translations; Validation; Vascular remodeling; analog; biomedical imaging; design; dosimetry; functional disability; imaging capabilities; imaging probe; in vivo; inhibitor; malignant breast neoplasm; molecular imaging; muscle physiology; nonhuman primate; pathogen; programs; radiotracer; rational design; scaffold; systemic inflammatory response; trait; transplant model; uptake

TR&D 3 Project Summary Reactive oxygen species (ROS) regulate critical physiological functions. However, the imbalance in production/mitigation of ROS also mediates pathogenesis of numerous diseases ranging from cardiovascular sciences to oncology clinic. Through the current funding cycle of TR&D3 program, we have identified a lead PET tracer (described herein as {68Ga}Galuminox) for imaging systemic inflammation and demonstrate its ability to monitor LPS-induced inflammation within lungs (acute lung injury model), monitor β3 integrin-mediated chemoresistance in breast cancer bone metastases, and kidney injury in nephrotic syndrome model. Importantly, Galuminox provides a sensitive readout of mitochondrial ROS (mROS) in human cells. Combined data indicate make {68Ga}Galuminox a worthy candidate of its advancement for regulatory approvals to evaluate safety through human dosimetry studies. Given its desirable trait to serve as a redox sensitive reporter probe, Galuminox also provides a template scaffold for generation and validation of copper-64 or fluorine-18 counterparts (with shorter positron range) as alternative PET tracers. Unfortunately, Galuminox analogues would not penetrate blood brain barrier (BBB) thus limiting their utility for assessing ROS mediated systemic inflammation. To achieve functional imaging of mROS within the brain, we have rationally designed small heterocyclic molecule ({18F}SLN128). Like Galuminox, SLN-128 is a highly fluorescent probe thus allowing opportunities for dual optical-PET readout for its biochemical validations. Compared with Galuminox which detects superoxide and hydrogen peroxide, SLN128 detects superoxide and hydroxyl radical. Given that both radiotracers have two different PET radionuclides and offer different detection capabilities, we anticipate that both PET molecular imaging probes could provide complementary information of oxidative imbalance mediating pathogenesis of both non-CNS and CNS diseases. Specific aims of TRD3 renewal are: Aim 1: Evaluate safety of {68Ga}Galuminox through human dosimetry studies following regulatory approvals. Aim 1.1: Evaluate the performance of {68Ga}Galuminox for imaging inflammation using rodent models of ischemic- and bacterial exotoxin-induced acute lung injury as well as other models of oxidative stress acute respiratory distress syndrome (ADRS), cystathionine γ-lyase (CSE) -mediated ischemic vascular remodeling, and meningeal ROS in MS through the Collaborative Projects. Aim1.2: To compensate for higher positron range of gallium-68 in Galuminox and allow options for delayed imaging in gastrointestinal tract, we propose to synthesize, biochemically characterize Cu-64 and F-18 counterparts of Galuminox and evaluate their pharmacokinetic profiles in diseased rodent models. Aim 1.3: As an exploratory aim, we also propose to design and develop small organic heterocyclic molecules for assessment of mROS prevalent in pathogenesis of neurodegenerative diseases. These products and those developed in the current grant cycle will be provided to our Service Projects as well.

TR＆D 3项目摘要 活性氧（ROS）调节关键生理功能。但是，不平衡 ROS的生产/缓解还介导了许多疾病的发病机理，范围从心血管 肿瘤学诊所的科学。通过当前TR＆D3计划的融资周期，我们已经确定了铅宠物 示踪剂（本文描述为{68ga} galuminox）用于成像全身注射，并证明了其能力 监测LPS引起的肺内炎症（急性肺损伤模型），监测β3整合素介导的 乳腺癌骨转移的化学耐药性和肾病综合征模型中的肾脏损伤。重要的是， Galuminox提供了人类细胞中线粒体ROS（MRO）的敏感读数。指示的组合数据 使{68GA}甘霉素成为其促进监管部门批准的致命候选者，以评估安全性 通过人类剂量学研究。鉴于其理想的特征是用作氧化还原敏感的记者探针 Galuminox还提供了一个模板支架，用于生成和验证铜64或氟-18 对应物（较短的正电子范围）作为替代宠物示踪剂。不幸的是，galuminox类似物会 不能穿透血脑屏障（BBB），从而限制了其评估ROS介导的全身性的效用 炎。为了实现大脑内MRO的功能成像，我们的理性设计很小 杂环分子（{18f} SLN128）。像Galuminox一样，SLN-128是一种高度荧光探针，因此允许 双重光PET读数的生化验证的机会。与galuminox相比 检测超氧化物和过氧化氢，SLN128检测到超氧化物和羟基自由基。鉴于这两个 放射性示例具有两个不同的宠物放射线，并提供不同的检测功能，我们预计 两个PET分子成像问题都可以提供介导的氧化失衡的完整信息 非CN和CNS疾病的发病机理。 TRD3更新的具体目标是：AIM 1：评估安全性 在监管批准后，通过人类剂量法研究的{68GA}甘霉素的作品。目标1.1：评估 使用缺血性和细菌的啮齿动物模型进行成像注射的{68GA} galuminox的性能 外毒素诱导的急性肺损伤以及其他氧化应激急性呼吸窘迫 综合征（ADR），胱淀粉γ-裂解酶（CSE）介导的缺血性血管重塑和脑膜ROS 在MS中通过协作项目。 AIM1.2：补偿较高的镀具有 Galuminox并允许在胃肠道中延迟成像的选项，我们建议合成， 生物化学表征了galuminox的Cu-64和F-18对应物，并评估其药代动力学 在不同啮齿动物模型中的轮廓。目标1.3：作为探索目的，我们还建议设计和开发 小的有机杂环分子，用于评估神经退行性发病机理中普遍存在的MROS 疾病。这些产品以及当前赠款周期中开发的产品将提供给我们的服务项目 也是如此。