Development of Tc-99m Renal Tubular Agents

描述（来自申请人摘要的逐字逐句）：我们寻求支持， 开发一种新的非侵入性，成本效益，准确，可重复的措施 有效肾血浆流量（ERPF），以加强患者的护理 肾功能受损，并促进机制研究， 肾脏疾病的治疗。我们的目标是开发新的阴离子和 阳离子Tc-99 m肾脏药物的清除率高于 停止使用的示踪剂，I-131邻碘马尿酸（OIH）和金的等效物 ERPF标准品，对氨基马尿酸盐（PAH）。我们的方法的可行性是 事实证明，我们的NIH资助的项目已经导致了 确定两个最好的第一代管状成像示踪剂， 人类，一项专利，以及五种有前途的新制剂的开发， Tc 99 m巯基乙酰三甘氨酸（MAG 3），商业上最好的代理 在美国，MAG 3具有严重的局限性。它的清除并不 测量标准肾功能参数，并且小于 PAH;此外，MAG 3不能可靠地检测肾功能的变化， 为35%。我们假设，最佳示踪剂将最小限度地绑定到 红细胞和血浆蛋白，并将具有关键的化学特征， 经验，以提供较高的肾脏清除率。为了验证这些假设，我们将 采用多方面的方法。我们提出（目标1）三类代理， 包括大部分未开发的阳离子肾示踪剂， 突破性研究和提高诊断准确性的潜力。最 这三类中的Tc-99 m试剂将利用新的配体，每种配体由 一种创新的方法（通过试剂盒制备）仅产生一种稳健的解决方案 对于所有的代理商，我们将确定 流线型动物肾脏排泄的生物分布、速率和特异性 模型（目标2）;最佳示踪剂将在人体研究中进行评估（目标3）。 目标2和3的结果将迭代地指导代理设计的修改 目标1。最佳示踪剂的剂量学至少相当于OIH， 人类将被确定（目标4）。ERPF的准确测量将具有 对肾前性肾病患者的诊断和治疗有重要影响 氮质血症这种情况发生在3- 5%的住院患者中， 当持续时，是缺血性肾小管坏死的最常见原因。一 上级ERPF示踪剂还将改善肾功能不全患者的管理。 肾功能不全，尤其是肾功能不稳定的患者，包括 例如肾移植、糖尿病和药物肾毒性。 最后，我们最近成功地识别了高清除率的示踪剂， 依赖于我们在锝和锝化学以及配体方面的进展， 设计与合成这些预付款和预计将从联合国收到的额外预付款 建议的工作是重要的，因为他们也将帮助其他人在 开发非肾Tc-99 m诊断剂和p-发射Re-186， Re-188治疗剂。

DESCRIPTION (Verbatim from the Applicant's Abstract): We seek support to develop a new non-invasive, cost effective, accurate, and reproducible measure of effective renal plasma flow (ERPF) to enhance the care of patients with impaired renal function and to facilitate research into the mechanisms and treatment of renal diseases. Our objective is to develop new anionic and cationic Tc-99m renal agents with a clearance higher than that of the discontinued tracer, I-131 ortho-iodohippuran (OIH) and equivalent to the gold standard of ERPF, para-aminohippurate (PAH). The feasibility of our approach is demonstrated by the fact that our NIH-funded program has already led to the identification of two of the best first-generation tubular imaging tracers in humans, one patent, and the development of five promising new agents comparable in rats to Tc99m mercaptoacetyltriglycine (MAG3), the best agent commercially available in the U.S. MAG3 has serious limitations. Its clearance does not measure a standard renal functional parameter and is less than half that of PAH; moreover, MAG3 cannot reliably detect changes in renal function as great as 35 percent. We hypothesize that an optimal tracer will be minimally bound to red cells and plasma proteins and will have key chemical features shown by experience to give a high renal clearance. To test these hypotheses, we will utilize a multifaceted approach. We propose (Aim 1) three classes of agents, including the largely unexplored cationic renal tracers, which offer the potential for breakthrough research and enhanced diagnostic accuracy. Most Tc-99m agents in the three classes will utilize novel ligands, each designed by an innovative approach to yield (via kit preparation) only one robust solution species at physiological pH. For all agents we will determine the biodistribution, rate and specificity of renal excretion in streamlined animal models (Aim 2); the best tracers will be assessed in human studies (Aim 3). Results from Aims 2 and 3 will iteratively direct modifications of agent design in Aim 1. The dosimetry of the best tracers at least equivalent to OIH in humans will be determined (Aim 4). An accurate measure of ERPF will have a significant impact on the diagnosis and management of patients with prerenal azotemia. This condition occurs in 3-5 percent of hospitalized patients and, when sustained, is the most common cause of ischemic tubular necrosis. A superior ERPF tracer will also improve the management of patients with renal insufficiency, especially those with unstable renal function, including conditions such as renal transplantation, diabetes, and drug nephrotoxicity. Finally, our recent success identifying tracers with high clearance has depended on our advances in technetium and rhenium chemistry and in ligand design and synthesis. These advances and additional advances expected from the proposed work are significant because they will also aid others in the development of non-renal Tc-99m diagnostic agents and of p-emitting Re-186 and Re-188 therapeutic agents.