Development of Tc-99m Renal Tubular Agents

描述（由申请人提供）： 800万美国成年人患有肾脏疾病。我们寻求加强对肾脏疾病患者的护理，并通过设计新型阴离子和阳离子99 m/Tc示踪剂来促进对肾脏和相关疾病的机制和治疗的研究，以开发一种新的探针，用于非侵入性，成本效益高，准确和可重复的有效肾血浆流量（ERPF）测量。具体而言，我们的目标是开发一种99 m/Tc示踪剂，其肾脏清除率高于已停用的131/I-邻碘马尿酸（OIH），并相当于ERPF金标准对氨基马尿酸盐（PAH）。我们的方法的可行性通过以下事实得到证明：我们的NIH计划已经鉴定了三种最好的人类第一代肾小管成像示踪剂（MAG 3，DD-EC，syn-DMAEC），一项专利，以及最近基于动物研究的两种有前途的新药物。99 m/Tc-巯基乙酰基三甘氨酸（MAG_3）是目前最好的商业化试剂，但存在严重的局限性。MAG 3清除率不到PAH的一半，Lots测量标准肾功能参数，不能可靠地显示高达35%的肾功能变化。 我们假设，最佳示踪剂将具有最小的红细胞和血浆蛋白结合，并将具有经验显示的关键化学特征，以提供高的肾脏清除率。我们将利用多方面的方法来测试这些假设。我们提出（目的1）通过利用我们在配体设计方面的广泛背景来制备适合于试剂盒制剂的新型示踪剂[这些示踪剂将包含传统的{Tc（V）O} 3+核心以及{Tc（CO）3} +和{Tc（V）N} 2+核心，这些核心尚未在肾脏药物中广泛探索，以及一些新的配体，其结合了（除其他特征外）：镧系元素骨架和丝氨酸]; (Aim 2）确定每种试剂在流线型动物模型中的生物分布以及肾排泄的速率和特异性;（目的3）评估人类中的最佳示踪剂[来自目的2和3的结果将迭代地指导目的1中的试剂设计的修改];（4）制备最佳药物进行临床试验。上级ERPF示踪剂将（1）帮助评估氮质血症患者，特别是那些疑似梗阻的患者，（2）提供简单、准确的测试来监测肾功能的变化，（3）影响肾前性氮质血症患者的诊断和管理，（4）促进诸如高血压和糖尿病的主要疾病的病理生理学的研究，最后（5）我们最近在鉴定具有高清除率的示踪剂方面的成功利用了我们在Fc和Re化学以及配体设计和合成方面的进展;这些和预期从拟议工作中获得的额外进展将有助于其他人开发非肾99 m/Tc诊断剂和β-放射性186 Re和188 Re治疗剂，特别是因为后者经常受到我们的药剂特别设计以避免的高肾滞留的困扰。

DESCRIPTION (provided by applicant): Eight million U.S. adults have kidney disease. We seek to enhance the care of patients with kidney disease and to facilitate research into the mechanisms and treatment of both kidney and related diseases by designing novel anionic and cationic 99m/Tc tracers to develop a new probe for the non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF). Specifically, our goal is to develop a 99m/Tc tracer with a higher renal clearance than the discontinued 131/I-ortho-iodohippuran (OIH) and equivalent to the ERPF gold standard, paraaminohippurate (PAH). The feasibility of our approach is demonstrated by the fact that our NIH program has already led to the identification of three of the best first-generation tubular imaging tracers in humans (MAG3, DD-EC, syn-DMAEC), one patent, and recently two promising new agents based on animal studies. 99m/Tc-mercaptoacetyltriglycine (MAG3), the best commercial agent, has serious limitations. The MAG3 clearance is less than half that of PAH, does Lotmeasure a standard renal functional parameter and cannot reliably reveal changes in renal function as great as 35%. We hypothesize that an optimal tracer will have minimal red cell and plasma protein binding and will have key chemical features shown by experience to give high renal clearances. We will utilize a multifaceted approach to test these hypotheses. We propose to (Aim 1) prepare novel tracers amenable to kit formulation by exploiting our extensive background in ligand design [These tracers will contain the traditional {Tc(V)O} 3+ core as well as the {Tc(CO)3} + and {Tc(V)N} 2+cores, not yet widely explored in renal agents, and some novel ligands incorporating, among other features, :he lanthionine backbone and serine.]; (Aim 2) determine each agent's biodistribution and rate and specificity of renal _xcretion in streamlined animal models; (Aim 3) assess the best tracers in humans [Results from Aims 2 and 3 will iteratively direct modifications of agent design in Aim 1.]; and (Aim 4) prepare the best agent for clinical trials. A superior ERPF tracer will (1) aid the evaluation of azotemic patients, especially those with suspected obstruction, (2) Provide a simple, accurate test to monitor changes in renal function, (3) impact the diagnosis and management ot patients with prerenal azotemia, (4) facilitate research in the pathophysiology of major diseases such as hypertension md diabetes, and finally (5) our recent success in identifying tracers with high clearance has drawn on our advances in Fc and Re chemistry and in ligand design and synthesis; these and additional advances expected from the proposed work will aid others in developing non-renal 99m/Tc diagnostic agents and beta-emitting l86Re and 188Re therapeutic agents, especially since the latter are often plagued by the high kidney retention our agents are specifically designed to avoid.