DEVELOPMENT OF TC-99M RENAL TUBULAR AGENTS

TC-99M肾小管制剂的研制

• 批准号: 3238383
• 负责人: ANDREW Thompson TAYLOR
• 金额: $ 17.16万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3238383
• 关键词: chemical synthesis; drug metabolism; human subject; image processing; laboratory mouse; laboratory rabbit; laboratory rat; radionuclide diagnosis; radiopharmacology; renal ischemia /hypoxia; renal tubular transport; technetium

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.

第一代肾小管剂Tc-99m巯基乙酰三甘氨酸 (MAG3)，在 NIH 资助的这项研究的前 3 年期间开发 正在进行 III 期临床试验。 开发出优秀的试剂盒配方 Mallinckrodt 生产的 MAG3 产率为 97%。 改进的成像特性 MAG3 使其成为替代 I-131 马尿酸 (OIH) 的可行显像剂，但 该试剂盒制剂的血浆清除率仍仅为OIH的49%。 获得清除率等于有效肾血浆的最佳药物 流量 (ERPF)，即几乎是纯 MAG3 的两倍，新 配体是根据成功的 MAG3 核心结构设计的。 配体设计将通过选定的分子图形建模得到增强 代理确定负责两者最佳的结构组件 和次优的管状运输。 新配体将与 Tc- 络合 99m 并与小鼠和大鼠的 OIH 进行比较。 高毒物毒性测试 将进行有前途的药物以及药代动力学和辐射 在人类受试者中测定的剂量测定。 二级间隙较高 新一代Tc-99m管状药剂将进一步提高图像质量，目标 与背景比，大大提高了检测的准确性和可靠性 定量测量，并可提供肾功能的直接测量 血浆流。 此外，综合体的改善将促进发展 评估输尿管功能的新测试。 辐射剂量为 肾功能受损的患者将进一步减少丹 改进的试剂将最大限度地减少双同位素（OIH 和 DTPA 或 OIH 和 MAG3) 肾脏研究，从而降低医疗费用。 MAG3 的诊断潜力将与 OIH 和碘酞酸盐进行比较 在临床相关的啮齿动物肾损伤模型中。 的一个主要焦点 啮齿类动物研究的敏感性、特异性和局限性 卡托普利挑战肾图检查，包括卡托普利与 其他已知会影响 GFR 和肾血流量的药物，如阿司匹林、 钙通道阻滞剂、β阻滞剂和心房自然因子。 这 动物研究将有助于指导 Tc-99m MAG3 的临床应用 当它上市时并阐明 MAG3、OIH 的作用 和 GFR 肾图筛查肾血管性高血压。