DEVELOPMENT OF TC-99M RENAL TUBULAR AGENTS

第一代肾小管剂--~(99)m-巯基乙酰甘氨酸 (MAG3)，在这项由美国国立卫生研究院赞助的研究的前3年开发 正在进行第三阶段的临床测试。开发了一种出色的试剂盒配方 Mallinckrodt的MAG3得率为97%。改进的成像特性 MAG3使其成为替代I-131马尿酸盐(OIH)的一种可行的显像剂，但 KIT制剂的血浆清除率仍仅为OIH的49%。 以获得清除量等于有效肾血浆的最佳试剂 Flow(Erpf)，即几乎是基本上纯MAG3的两倍，新 在MAG3核心结构成功的基础上进行了配体的设计。 配基设计将通过选定的分子图形建模来增强 代理商要确定对两者负责的最优结构部件 和次优的管状运输。新的配体将与TC-络合 99m，并与OIH小鼠和大鼠进行比较。高密度脂蛋白毒性试验 有希望的药物将执行和药代动力学和辐射 在人体内测定的剂量学。秒的较高净空 新一代TC-99M管状剂将进一步提高图像质量，目标 与背景比相比，大大提高了检测的准确性和可靠性 定量测量，并可提供肾脏的直接测量 等离子体流。此外，改进后的综合体将促进发展 一种评估输尿管功能的新测试。达到的辐射剂量 肾功能受损的患者将进一步减少 改进的试剂将最大限度地减少对双同位素(OIH和DTPA或OIH)的需求 和MAG3)肾脏研究，从而降低医疗成本。 MAG3的诊断潜力将与OIH和硫代氨基甲酸酯进行比较 在临床相关的肾损伤啮齿动物模型中。会议的一个主要焦点是 啮齿动物研究将是敏感性、特异性和局限性 卡托普利挑战肾造影术，包括卡托普利与 其他已知会影响肾小球滤过率和肾血流的药物，如阿司匹林， 钙通道阻滞剂、β阻滞剂和心钠素。这个 动物实验将有助于指导~(99m)Tc-MAG3的临床应用 当MAG3上市并阐明MAG3的作用时，OIH 肾小球滤过率在肾血管性高血压筛查中的应用。

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.