Development of Tc-99m Renal Tubular Tracers

描述（由申请人提供）：在过去的十年中，慢性肾脏疾病增加了30%，目前估计有2700万美国人受到影响，占所有医疗保险费用的24%以上。迫切需要有效的策略来发现早期肾脏疾病，监测治疗过程，延缓进展，提高诊断准确性。为了满足这些需求，我们的主要目标是完成新型阴离子99mTc探针的开发和初步人体评估，用于无创、经济高效、准确和可重复的有效肾血浆流量（ERPF）测量。131i -邻碘希波兰（OIH）是测量ERPF的临床标准，已不再市售，而99mTc-巯基乙酰甘油三酯（MAG3）是FDA批准的最佳药物，广泛使用99mTc，但存在严重局限性。MAG3清除率仅为OIH的50-60%，不能测量标准的肾功能参数，不能可靠地检测肾功能变化小于35%。我们的方法的可行性证明了我们的NIH项目已经导致(1)鉴定出最好的第一代99mTcO肾示踪剂：MAG3， DD-EC, syn-D-MAEC；(2)新型99mTc(CO)3示踪剂，包括极具前景的99mTc(CO)3硝基三乙酸（NTA）示踪剂；（三）一项专利；(4)一项临时专利，(5)首个99mTc(CO)3肾示踪剂在人体中进行评估。99mTc(CO)3 （NTA）是一种单一物种，适合试剂盒配方，根据对5名志愿者的研究，其清除率相当于131I-OIH。第二个重要的目标是推进Tc和Re（铼）化学和配体设计，实现我们的主要目标的过程将完成。具体来说，我们建议(1)通过关注促进{Tc(I)(CO)3}+核心化学的配体来制备适合试剂盒配方的新型示踪剂，采用创新的配体设计和强大的溶液形态形成方法应用于Re类似物，特别是当供体基团倾向于单一的非手性99mTc阴离子剂时；(2)确定每种新型示踪剂的药代动力学，特别是流线型动物模型的肾排泄率和特异性；(3)测定人体药代动力学和剂量学，并利用结果加强示踪剂的设计；(4)在相关患者群体中进行重点人体研究，比较NTA（和其他合适的示踪剂）与OIH和MAG3的图像质量。一种优质的ERPF示踪剂将(1)提高诊断准确性，特别是对患有azotemia的儿童和疑似梗阻的成人患者，(2)提供一种简单、准确的检测和监测肾小管功能变化的方法，(3)协助肾小管功能障碍患者的诊断和护理，(4)促进早期发现肾小管功能障碍和预防肾脏疾病的基础和临床研究。(5)帮助其他人开发非肾脏99mTc诊断示踪剂和2-发射186Re和188Re治疗剂，因为我们的制剂专门设计用于避免困扰Re治疗剂的高肾潴留。我们已接近成功，并预计下一个资助期将使该项目完成。公共卫生相关性：在过去的十年中，慢性肾脏疾病增加了30%，目前估计有2700万美国人受到影响，占所有医疗保险费用的24%以上。为了改善对已知或疑似肾脏疾病患者的治疗，支持对肾小管功能机制和肾脏疾病预防的基础和临床研究，我们的主要目标是开发一种用于肾脏成像和监测肾小管功能的新型放射性示踪剂。在我们的研究中使用的放射性同位素是锝99m，它在美国和所有发达国家广泛使用，在大多数发展中国家和许多第三世界国家的主要城市都可以使用。我们的第二个目标是提高对锝化学和锝放射性药物开发的理解，以便本项目中对锝的基础研究将促进其他人开发新的非肾脏诊断性锝成像示踪剂以及与锝具有相同化学性质但可用于治疗的铼放射性药物。

DESCRIPTION (provided by applicant): The past decade has seen a 30% increase in chronic kidney disease, which now affects an estimated 27 million Americans and accounts for more than 24% of all Medicare costs. Effective strategies are urgently needed to detect early renal disease, monitor the course of therapy, retard progression, and enhance diagnostic accuracy. To meet these needs, our primary objective is to complete the development and initial human evaluation of novel anionic 99mTc based probes for the non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF). 131I-ortho-iodohippuran (OIH), the clinical standard for measuring the ERPF, is no longer commercially available and 99mTc-mercaptoacetyltriglycine (MAG3), the best FDA approved agent using widely available 99mTc, has serious limitations. The MAG3 clearance is only 50-60% that of OIH, does not measure a standard renal functional parameter, and cannot reliably detect a change in renal function less than 35%. The feasibility of our approach is demonstrated by the fact that our NIH program has already led to (1) the identification of the best first-generation 99mTcO renal tracers: MAG3, DD-EC, syn-D-MAEC; (2) new 99mTc(CO)3 tracers including the highly promising 99mTc(CO)3 nitrilotriacetic acid (NTA) tracer; (3) one patent; (4) a provisional patent, and (5) the first 99mTc(CO)3 renal tracer to be evaluated in humans. 99mTc(CO)3 (NTA) is a single species, is amenable to kit formulation and has a clearance equivalent to 131I-OIH based on studies in five volunteers. An important second objective is to advance Tc and Re (rhenium) chemistry and ligand design, which the process of achieving our primary objective will accomplish. Specifically, we propose to (1) prepare novel tracers amenable to kit formulation by focusing on ligands that advance the chemistry of the {Tc(I)(CO)3}+ core, with innovative ligand design and powerful solution speciation methods applied to Re analogs especially where the donor groups favor a single preferably non-chiral 99mTc anionic agent; (2) determine the pharmacokinetics of each new tracer, especially the rate and specificity of renal excretion in streamlined animal models; (3) determine the pharmacokinetics and dosimetry in humans and use the results to enhance tracer design; and (4) conduct focused human studies comparing image quality of NTA (and other suitable tracers) with OIH and MAG3 in relevant patient populations. A superior ERPF tracer will (1) enhance diagnostic accuracy, particularly in azotemic pediatric and adult patients with suspected obstruction, (2) provide a simple, accurate test to detect and monitor changes in tubular function, (3) assist the diagnosis and care of patients with prerenal azotemia, (4) facilitate basic and clinical research for the detection of early tubular dysfunction and the prevention of renal disease, and (5) aid others in developing non-renal 99mTc diagnostic tracers and 2-emitting 186Re and 188Re therapeutic agents, because our agents are specifically designed to avoid the high kidney retention plaguing Re therapeutic agents. We are close to success and anticipate that the next funding period will bring this project to completion. PUBLIC HEALTH RELEVANCE: The past decade has seen a 30 percent increase in chronic kidney disease which now affects an estimated 27 million Americans and accounts for more than 24% of all Medicare costs. To improve the treatment of patients with known or suspected renal disease and to support basic and clinical research into the mechanisms of renal tubular function and the prevention of renal disease, our primary objective is to develop a new radioactive tracer for imaging the kidney and monitoring renal tubular function. The radioactive isotope used in our studies is technetium 99m which is widely available in the US, all developed countries and is available in the major cities of most developing and many third world nations. Our secondary objective is to enhance the understanding of technetium chemistry and technetium radiopharmaceutical development so that the basic technetium research in this project will facilitate the development by others of new non-renal diagnostic technetium imaging tracers as well as rhenium radiopharmaceuticals which have an identical chemistry to technetium but which can be used for therapy.