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）调节重要的生理功能。然而， ROS的产生/减轻还介导许多疾病的发病机制， 科学到肿瘤诊所通过当前的TR&D3项目资助周期，我们已经确定了一个牵头的PET 示踪剂（本文描述为{68 Ga} Galaluminox）用于全身性炎症成像，并证明其 监测肺内LPS诱导的炎症（急性肺损伤模型），监测β3整合素介导的 乳腺癌骨转移中的化学抗性和肾病综合征模型中的肾损伤。重要的是， Galallox提供人细胞中线粒体ROS（mROS）的灵敏读数。综合数据显示 使{68 Ga} Galalumox成为监管部门批准评估安全性的有价值的候选产品 通过人体剂量学研究。考虑到其作为氧化还原敏感报告探针的理想特性， Galallox还提供了一种模板支架，用于铜-64或氟-18的生成和验证 对应物（具有较短的正电子范围）作为替代PET示踪剂。不幸的是，Galalumox类似物 不能穿透血脑屏障（BBB），因此限制了它们用于评估ROS介导的系统性 炎症为了实现脑内mROS的功能成像，我们合理地设计了小的 杂环分子（{18 F} SLN 128）。与Galalumox一样，SLN-128是高荧光探针，因此允许 双光学PET读出的机会，其生化验证。与Galalumox相比， SLN 128检测超氧阴离子和羟自由基。鉴于双方 放射性示踪剂有两种不同的PET放射性核素，并提供不同的检测能力，我们预计， 两种PET分子成像探针都可以提供氧化失衡介导的互补信息， 非CNS和CNS疾病的发病机制。TRD 3更新的具体目的是：目的1：评价安全性 在获得监管机构批准后，通过人体剂量测定研究获得{68 Ga} Galalumox。目标1.1：评估 使用缺血性和细菌性的啮齿动物模型，{68 Ga} Galaluminox用于成像炎症的性能 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模型 综合征（ADRS）、胱硫醚γ-裂解酶（CSE）介导的缺血性血管重塑和脑膜ROS 通过合作项目在MS。目标1.2：为了补偿镓-68在 Galallox并允许胃肠道延迟成像的选择，我们建议合成， 对Galalumox的Cu-64和F-18对应物进行生物化学表征，并评估其药代动力学 在患病啮齿动物模型中的分布。目标1.3：作为探索性目标，我们还建议设计和开发 小有机杂环分子用于评估神经退行性疾病发病机制中普遍存在的mROS 疾病这些产品和在当前资助周期内开发的产品将提供给我们的服务项目 也