Functional PET Imaging of Oxidative Stress

描述(申请人提供)：针对特定生物标记物的分子显像剂正变得越来越普遍，以使个性化医学成为可能。开发新的靶向显像剂或疗法的成本可能会对经济造成不利影响，因为许多靶向试剂只会影响相对较小的人群部分。正电子发射断层扫描(PET)试剂18F-氟代脱氧葡萄糖(18FDG)的成功归功于它的目标是一种普遍存在的机制，即葡萄糖摄取，这是提高细胞新陈代谢所必需的，已发现从肿瘤学到心脏和大脑功能的广泛临床相关性。我们建议开发一类新的PET显像剂，作为分子转运蛋白的底物，这种转运蛋白在细胞对氧化应激做出反应时被普遍激活。为了将该运输系统用作一种新的成像生物标记物，转运体必须具有足够的混杂以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，并证明了在肿瘤体内摄取半胱氨酸被证实为转运蛋白活性。这项建议的目标是开发最好的母体底物和放射性标记的组合，以最大限度地提高转运效率，并展示细胞氧化应激的体内成像。氧化应激PET显像剂具有潜在的广泛用途，可用于包括细胞氧化应激在内的许多适应症，包括神经退行性疾病、动脉粥样硬化、缺血、器官移植排斥反应、自身免疫性疾病、炎症性疾病、肿瘤学和衰老。

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.