DEVELOPMENT OF TC-99M RENAL TUBULAR AGENTS

第一代肾小管抑制剂Tc-99 m巯基乙酰三甘氨酸 （MAG 3），在NIH赞助的这项研究的前3年开发的 正在进行III期临床试验 开发了一种出色的试剂盒配方 由Mallinckrodt得到97%的MAG 3。 改进的成像特性， MAG 3使其成为替代I-131马尿酸盐（OIH）的可行的成像剂， 药盒制剂的血浆清除率仍然仅为OIH的49%。 获得清除率等于有效肾血浆的最佳药物 流动（ERPF），即几乎是基本纯MAG 3的两倍，新的 基于成功的MAG 3核心结构设计了配体。 配体设计将通过选择的分子图形建模来增强。 代理人，以确定负责两个最佳的结构组件， 和次优的肾小管转运。 新的配体将与Tc- 99 m，并与小鼠和大鼠中的OIH进行比较。 毒性试验高 有前途的药物将进行和药代动力学和辐射 在人类受试者中确定的剂量测定。 第二个更高的间隙 新一代Tc-99 m管状剂将进一步改善图像质量，靶向 与背景比，大大提高了准确性和可靠性， 定量测量，并且可以提供肾功能的直接测量。 等离子体流 此外，改进的复合体将促进发展 一种新的测试来评估输尿管功能。 的辐射剂量 肾功能受损的患者， 改进的试剂将使对双同位素（OIH和DTPA或OIH）的需要最小化 和MAG 3）肾研究，从而降低医疗费用。 将MAG 3的诊断潜力与OIH和碘酞酸盐进行比较 在临床相关的啮齿动物模型中的肾损伤。 的一大重点 啮齿动物研究将是敏感性，特异性和局限性， 巯甲丙脯酸激发肾造影术，包括巯甲丙脯酸与 其他已知影响GFR和肾血流的药物如阿司匹林， 钙通道阻滞剂、β受体阻滞剂和心房利钠因子。 的 动物实验将有助于指导Tc-99 mMAG 3的临床应用 并澄清MAG 3、OIH的作用 和GFR肾图筛查肾血管性高血压。

A first generation renal tubular agent, Tc-99m mercaptoacetyltriglycine (MAG3), developed during the first 3 years of this NIH-sponsored research is in Phase III clinical testing. An excellent kit formulation developed by Mallinckrodt yields 97% MAG3. The improved imaging characteristics of MAG3 make it a viable imaging agent for replacing I-131 hippurate (OIH) but the plasma clearance of the kit formulation is still only 49% that of OIH. To obtain an optimal agent with a clearance equal to effective renal plasma flow (ERPF), i.e. almost twice that of the essentially pure MAG3, new ligands have been designed based on the successful MAG3 core structure. Ligand design will be enhanced by molecular graphics modeling of selected agents to determine the structural components responsible for both optimal and suboptimal tubular transport. New ligands will be complexed with Tc- 99m and compared to OIH in mice and rats. Toxicity testing of highly promising agents will be performed and the pharmacokinetics and radiation dosimetry determined in human subjects. The higher clearance of second generation Tc-99m tubular agents will further improve image quality, target to background ratio, greatly increase the accuracy and reliability of quantitative measurements, and may provide a direct measurement of renal plasma flow. Furthermore, improved complexes will facilitate development of a new test to evaluate ureteral function. The radiation dose to patients with impaired renal function will be further reduced an dan improved agent will minimize the need for dual isotope (OIH and DTPA or OIH and MAG3) renal studies thereby reducing medical costs. The diagnostic potential of MAG3 will be compared with OIH and iothalamate in clinically relevant rodent models of renal injury. A major focus of the rodent research will be the sensitivity, specificity, and limitations of captopril challenge renography including coadministration of captopril with other medications known to affect GFR and renal blood flow such as aspirin, calcium channel blockers, beta blockers and atrial naturetic factor. The animal studies will help direct the clinical applications of Tc-99m MAG3 when it becomes commercially available and clarify the role of MAG3, OIH and GFR renography in screening for renovascular hypertension.