Functional PET Imaging of Oxidative Stress

描述（由申请人提供）：靶向特定生物标志物的分子成像剂在实现个性化医疗的努力中变得越来越普遍。开发新的靶向成像剂或治疗剂的成本在经济上可能是不利的，因为许多靶向剂将影响相对较小的人群。正电子发射断层扫描（PET）试剂18 F-氟脱氧葡萄糖（18 FDG）的成功归功于它靶向一种普遍存在的机制，即葡萄糖摄取，这是增加细胞代谢所需的，已经发现从肿瘤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，这是一种分子转运蛋白的底物，这种分子转运蛋白在细胞对氧化应激的反应中被普遍激活。为了使该转运系统用作新的成像生物标志物，转运蛋白必须具有足够的混杂性以接受具有附加标签的底物。我们的团队已经证明了转运蛋白混杂性的这一重要里程碑，并证明了肿瘤中胱氨酸的体内摄取验证了转运蛋白活性。本提案的目标是开发最佳母体底物和放射性标记组合，以实现最大转运效率，并证明细胞氧化应激的体内成像。氧化应激PET成像剂将对包括细胞氧化应激的许多适应症具有潜在的广泛用途;包括神经变性疾病、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.