DEVELOPMENT OF TC-99M RENAL TUBULAR AGENTS

描述（改编自申请人的摘要）：本发明的目的是 应用是开发一种上级Tc-99 m肾小管转运显像 代理人，将提供一个准确的，可重复的，具有成本效益的， 快速测量有效肾血浆流量（ERPF）。 测量 ERPF将有助于肾前性肾病患者的诊断和管理 氮质血症发生在3-5%的住院患者中，并且当持续时， 是缺血性肾小管坏死的最常见原因。 这样的代理人将 还可以改善肾病患者的管理， 肾功能不稳定的患者（即，肾移植， 糖尿病、肾毒性药物）。 第一次Tc-99 m肾小管转运显像 代理人，[Tc-99]巯基乙酰基三甘氨酸（MAG 3），介绍了我们的 美国国立卫生研究院赞助的研究，有严重的局限性。 它的清除并不 测量一个标准的肾功能参数，小于一半， PAH，并且根据最近的数据，不能可靠地检测肾脏 功能高达35%。 我们的研究阐明了 最好的现有的Tc-99 m剂，特别是在溶液中，并导致 与有效的肾小管转运相关的假设特征， 设计一种上级试剂所需的低蛋白结合。 为了验证假设， 新配体的Tc-99 m络合物的清除和生物分布将是 在大鼠中测定;肾小球滤过和蛋白结合的影响 将使用微穿刺研究评价肾小管提取的影响， 离体灌流大鼠肾。 有希望的复合物将在正常条件下进行测试。 志愿者 最好的Tc-99 m配合物的结构将被评估 通过非放射性的铼（Re）络合物， 结构. 这些结构将以图形方式叠加， 确定重叠，并设计新的代理。 我们的迭代方法 已经导致了一类新的Tc-99 m配体以及3个新的管状 在初步的大鼠生物分布研究中有希望的药物。 除了 ERPF药物的临床优势应导致具有竞争力的价格 并且降低了管状示踪剂的成本。 MAG 3未得到充分利用，因为它 是诊断上较低的DTPA的14倍。 在 目前MAG 3的使用水平，管状剂的成本降低30%， 每年节省900万美元 降低成本也应该增加 可访问性;使用率增加10%将提供上级诊断 再增加2500万美国人。 最后，我们介绍了 多功能新型螯合物的有效构建模块路线， 对Tc和Re化学的理解的贡献将有助于 开发新的诊断（Tc-99 m）和治疗（Re-186和 Re-188）放射性药物。

DESCRIPTION (Adapted from Applicant's Abstract): The objective of this application is to develop a superior Tc-99m renal tubular transport imaging agent that would provide an accurate, reproducible, cost-effective, and rapid measurement of effective renal plasma flow (ERPF). Measurement of ERPF will aid in the diagnosis and management of patients with prerenal azotemia which occurs in 3-5% of hospitalized patients and, when sustained, is the most common cause of ischemic tubular necrosis. Such an agent will also improve the management of patients with renal disease, particularly those whose renal function may be unstable (i.e., renal transplantation, diabetes, nephrotoxic drugs). The first Tc-99m tubular transport imaging agent, [Tc-99] mercaptoacetyltriglycine (MAG3), introduced by our NIH-sponsored research, has serious limitations. Its clearance does not measure a standard renal functional parameter, is less than half that of PAH, and, based on recent data, cannot reliably detect changes in renal function as great as 35%. Our research has elucidated structural properties of the best existing Tc-99m agents, especially in solution, and led to hypotheses characteristics associated with efficient tubular transport and low protein binding needed to design a superior agent. To test hypotheses, the clearance and biodistribution of Tc-99m complexes of new ligands will be determined in rats; glomerular filtration and the effects of protein binding on tubular extraction will be evaluated using micropuncture studies and the isolated perfused rat kidney. Promising complexes will be tested in normal volunteers. The structures of the best Tc-99m complexes will be assessed through non-radioactive rhenium (Re) complexes which have comparable structures. The structures will be graphically superimposed, the points of overlap identified, and new agents designed. Our iterative approach has already led to a novel class of Tc-99m ligands as well as 3 new tubular agents promising in preliminary rat biodistribution studies. In addition to the clinical advantages an ERPF agent should result in competitive pricing and reduced costs for tubular tracers. MAG3 is under-utilized because it is 14 times as expensive as the diagnostically inferior agent, DTPA. At current levels of MAG3 use, a 30% reduction in cost of tubular agents would save 9 million dollars annually. Lower costs should also increase accessibility; a 10% increase in use would provide superior diagnostic studies to an additional 25 million Americans. Finally, our introduction of efficient building-block routes to versatile novel chelates and continued contributions to the understanding of Tc and Re chemistry will facilitate the development of new diagnostic (Tc-99m) and therapeutic (Re-186 and Re-188) radiopharmaceuticals.