PET Tracers for Imaging ROS Activity

R&D 3项目总结 活性氧(ROS)调节重要的生理功能。然而，中国经济的不平衡 ROS的产生/减轻也参与了多种疾病的发病，包括心血管疾病 科学部到肿瘤科诊所。通过当前的TR&D3计划的资金周期，我们已经确定了一个牵头的PET 用于全身炎症成像的示踪剂(在此描述为{68Ga)，并展示其能力 监测内毒素诱导的肺内炎症(急性肺损伤模型)，监测β3整合素介导的 乳腺癌骨转移和肾病综合征模型肾损害的化疗耐药。重要的是 Galnuox提供了人类细胞中线粒体ROS(MRO)的灵敏读数。综合数据显示 使{68Ga}GalLumox成为值得推广的候选产品，以获得监管部门的批准，以评估安全性 通过人体剂量学研究。鉴于其作为氧化还原灵敏的记者探针的可取特性， GalLumox还为铜的生成和验证提供了模板脚手架-或氟-18 (具有较短正电子射程的)作为替代的PET示踪剂。不幸的是，伽鲁米诺的类似物 不能穿透血脑屏障(BBB)，从而限制了它们在评估ROS介导的系统性疾病中的作用 发炎。为了在大脑内实现MRO的功能成像，我们合理地设计了小型 杂环分子({18F}SLN128)。与Galnuox一样，SLN-128是一种高度荧光的探针，因此可以 为其生化验证提供双光学-PET读数的机会。与伽鲁米诺克斯相比，加卢米诺克斯 SLN128检测超氧化物和过氧化氢，SLN128检测超氧化物和羟基自由基。鉴于两者都是 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氧化失衡调节的互补信息 非中枢神经系统疾病和中枢神经系统疾病的发病机制。TRD3更新的具体目标是：目标1：评估安全性 在监管部门批准后，通过人体剂量学研究对{68Ga]Galnuox进行研究。目标1.1：评估 ~(68)Ga}GalLumox在鼠类脑缺血和细菌模型炎症成像中的作用 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构和脑膜ROS 通过协作项目在MS中学习。目的1.2：补偿~(68)Ga的较高正电子射程。 Galnuox并允许在胃肠道延迟成像的选项，我们建议合成， 加路米诺铜-和F-18对映体的生化特征及其药代动力学研究 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 用有机杂环小分子评价神经退行性变发病机制中的MRO 疾病。这些产品和在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。

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.