Functional PET Imaging of Oxidative Stress

氧化应激的功能性 PET 成像

• 批准号: 8502492
• 负责人: Jack Mathew Webster
• 金额: $ 62.53万
• 依托单位: GENERAL ELECTRIC GLOBAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-02 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502492
• 关键词: Aging; Animal Model; Atherosclerosis; Autoimmune Diseases; Biodistribution; Biological Assay; Biological Markers; Brain; Cells; Cystine; Detection; Development; Disease; Drug Kinetics; Evaluation; Functional Imaging; Glutamate Transporter; Glutamates; Goals; Graft Rejection; Heart; Image; In Vitro; Inflammatory; Ischemia; Label; Lead; Medicine; Metabolism; Modeling; Modification; Neurodegenerative Disorders; Organ Transplantation; Outcome; Oxidative Stress; Parents; Population; Positron; Positron-Emission Tomography; Proteins; Radiolabeled; Sclerosis; Signal Transduction; Site; Structure-Activity Relationship; System; Therapeutic; Tissues; Up-Regulation; analog; cellular imaging; clinical application; clinically relevant; cost; fluorodeoxyglucose; glucose uptake; in vivo; in vivo Model; molecular imaging; molecular transporter; novel; oncology; radiotracer; response; success; tomography; tumor; uptake

DESCRIPTION (provided by applicant): Molecular imaging agents targeting specific biomarkers are becoming more prevalent in an effort to enable personalized medicine. The cost to develop novel targeted imaging agents or therapeutics can be economically detrimental as many targeted agents will impact relatively small segments of the population. The Positron Emission Tomography (PET) agent 18F-fluorodeoxyglucose (18FDG) owes its success to the fact that it targets a ubiquitous mechanism, glucose uptake, required for increased cellular metabolism that has found wide clinical relevance from oncology to heart and brain function. We propose to develop a novel class of PET imaging agents, which are substrates for a molecular transporter that is ubiquitously activated as cells response to oxidative stress. In orde for this transport system to be utilized as a novel imaging biomarker, the transporter must have sufficient promiscuity to accept substrates with an appended label. Our team has already demonstrated this vital milestone of transporter promiscuity and demonstrated in vivo uptake of cystine in tumors validated for transporter activity. The goal of this proposal is to develop the best parent substrate and radiolabel combination for maximal transport efficiency and to demonstrate in vivo imaging of cellular oxidative stress. An oxidative stress PET imaging agent would have a potential broad utility for many of the indications that include cellular oxidative stress; including neurodegenerative diseases, atherosclerosis, ischemia, organ transplant rejection, autoimmune diseases, inflammatory diseases, oncology and aging.

描述（由申请人提供）：靶向特定生物标志物的分子显像剂在实现个性化医疗的努力中变得越来越普遍。开发新型靶向显像剂或治疗方法的成本可能在经济上是有害的，因为许多靶向药物将影响相对较小的人群。正电子发射断层扫描（PET）剂18f -氟脱氧葡萄糖（18FDG）的成功归功于这样一个事实，即它针对一种普遍存在的机制，即葡萄糖摄取，这是增加细胞代谢所必需的，从肿瘤学到心脏和大脑功能已经发现了广泛的临床相关性。我们建议开发一种新型PET显像剂，它是一种分子转运体的底物，这种转运体在细胞对氧化应激的反应中无处不在地被激活。为了使这种转运系统被用作一种新的成像生物标志物，转运体必须具有足够的混杂性来接受带有附加标签的底物。我们的团队已经证明了转运蛋白混杂的这一重要里程碑，并证实了转运蛋白活性在肿瘤中胱氨酸的体内摄取。本提案的目标是开发最佳的母体底物和放射性标记组合，以获得最大的运输效率，并证明细胞氧化应激的体内成像。氧化应激PET显像剂在许多适应症中具有潜在的广泛用途，包括细胞氧化应激；包括神经退行性疾病、动脉粥样硬化、缺血、器官移植排斥、自身免疫性疾病、炎症性疾病、肿瘤和衰老。