Development of Tc-99m Renal Tubular Tracers

描述(申请人提供)：在过去的十年里，慢性肾脏疾病增加了30%，目前估计有2700万美国人受到影响，占所有联邦医疗保险成本的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，并提高诊断的准确性。为了满足这些需求，我们的主要目标是完成基于99mTc的新型阴离子探针的开发和初步人体评估，以无创、经济、准确和可重复性地测量有效肾血浆流量(ERPF)。测量ERPF的临床标准131I-邻碘马尿酸(OIH)已不再商业化，而FDA批准的使用广泛使用的99mTc的最佳试剂99mTC-硫代乙酰甘氨酸(MAG3)有严重限制。MAG3清除率仅为OIH的50%-60%，没有测量标准的肾功能参数，也不能可靠地检测到低于35%的肾功能变化。我们的方法的可行性体现在以下事实上：我们的NIH计划已经导致(1)确定了最好的第一代99mTcO肾脏示踪剂：MAG3、DD-EC、SYN-D-MAEC；(2)新的99mTc(CO)3示踪剂，包括非常有前途的99mTc(CO)3氮三乙酸(NTA)示踪剂；(3)一项专利；(4)临时专利；(5)第一个将在人体上进行评估的99mTc(CO)3肾脏示踪剂。99mTc(CO)3(NTA)是一种单一物种，可用于试剂盒制剂，基于对五名志愿者的研究，其清除量相当于131I-OIH。第二个重要的目标是推进Tc和Re(Re)的化学和配体设计，这是实现我们主要目标的过程中将实现的。具体地说，我们建议(1)通过专注于促进{TC(I)(CO)3}+核心化学的配体，利用创新的配体设计和强大的溶液形态形成方法应用于再类似物，特别是当供体基团倾向于单一的优选非手性99mTC阴离子试剂的情况下，制备可用于试剂盒配方的新型示踪剂；(2)在流线型动物模型中确定每种新示踪剂的药代动力学，特别是肾脏排泄的速率和特异性；(3)确定人体的药物动力学和剂量学，并利用结果来加强示踪剂的设计；以及(4)在相关患者群体中进行有针对性的人体研究，比较NTA(和其他合适的示踪剂)与OIH和MAG3的图像质量。卓越的ERPF示踪剂将(1)提高诊断准确性，尤其是对疑似梗阻的儿童和成人患者，(2)提供简单、准确的测试来检测和监测肾小管功能的变化，(3)协助肾前性氮质血症患者的诊断和护理，(4)促进基础和临床研究，以检测早期肾小管功能障碍和预防肾脏疾病，以及(5)帮助他人开发非肾脏99mTc诊断示踪剂和2-释放186Re和188Re治疗剂，因为我们的试剂是专门为避免高肾脏滞留而设计的。我们即将取得成功，并预计下一个资金期将使该项目完成。与公共健康相关：在过去的十年里，慢性肾脏疾病增加了30%，目前估计有2700万美国人受到影响，占所有医疗保险成本的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新的放射性示踪剂，用于肾脏成像和监测肾小管功能。我们研究中使用的放射性同位素是99m，它在美国和所有发达国家广泛可用，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用。我们的次要目标是加强对锶化学和氚放射性药物开发的了解，以便本项目中的基础锶研究将促进其他人开发新的非肾脏诊断氚成像示踪剂，以及与锶具有相同化学成分但可用于治疗的Re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.