PET Tracers for Imaging ROS Activity

用于 ROS 活动成像的 PET 示踪剂

基本信息

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
项目类别：
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&apos 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

项目摘要

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 项目摘要然而，活性氧（ROS）调节关键的生理功能。 ROS 的产生/减轻还介导多种疾病的发病机制，包括心血管疾病通过 TR&D3 计划当前的资助周期，我们已经确定了领先的 PET。示踪剂（本文描述为 {68Ga}Galuminox）用于对全身炎症进行成像并证明其能力监测 LPS 诱导的肺部炎症（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疗耐药性和肾病综合征模型中的肾损伤。 Galluminox 提供了人类细胞中线粒体 ROS (mROS) 的灵敏读数。使 {68Ga}Galuminox 成为值得监管部门批准以评估安全性的候选者通过人体剂量测定研究，鉴于其作为氧化还原敏感报告探针的理想特性， Galumox 还提供了用于生成和验证 Copper-64 或 Fluor-18 的模板支架遗憾的是，Galuminox 类似物无法替代 PET 示踪剂。不能穿透血脑屏障（BBB），从而限制了它们评估 ROS 介导的全身系统的效用为了实现大脑内mROS的功能成像，我们合理地设计了微小的炎症。与 Galumox 一样，SLN-128 是一种强荧光探针，因此可以实现。与 Galluminox 相比，双光学 PET 读数的机会。检测超氧化物和过氧化氢，SLN128 检测超氧化物和羟基自由基。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 分子成像探针均可提供介导氧化失衡的补充信息 TRD3 更新的具体目标是：目标 1：评估安全性。 {68Ga}Galuminox 在监管部门批准后通过人体剂量测定研究进行评估目标 1.1：评估 {68Ga}Galuminox 使用缺血性和细菌性啮齿动物模型对炎症进行成像的性能外毒素引起的急性肺损伤以及其他氧化应激模型急性呼吸窘迫综合征 (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 中进行目标 1.2：补偿镓 68 的较高正电子范围。 Galluminox 并允许选择胃肠道延迟成像，我们建议合成，对 Galuminox 的 Cu-64 和 F-18 分子进行生化表征并评估其药代动力学目标 1.3：作为一个探索性目标，我们还建议设计和开发。有机杂环小分子用于评估神经退行性疾病发病机制中普遍存在的 mROS 这些产品和当前资助周期中开发的产品将提供给我们的服务项目。以及。