Development of Tc-99m Renal Tubular Tracers

研究计划摘要：我们的主要目标是开发锝（99 mTc）和氟（* F）肾示踪剂 在人体中的清除率至少等于临床金标准，即1-碘马尿酸或1-碘马尿酸（1-OIH）， 接近对氨基马尿酸盐（PAH）的清除率。这些试剂应取代目前最好的示踪剂99 mTc-Tcinercaptoacetyltriglycine（99 mTc-MAGS）。正如本提交文件中所详述的，尽管由于老化反应堆的暂时关闭而导致iTiMo-99（99 mTc的母体同位素）的全球供应中断带来了挑战，但我们仍然取得了出色的进展。为了解决未来99 mTc的短缺问题，并利用PET固有的更好分辨率和PET扫描仪的广泛可用性，我们正在扩展我们最初的具体目标，使用创新的化学和配体设计来开发18F和99 mTc标记的肾脏示踪剂。 我们的第二个目标将在实现第一个目标的过程中实现， 理解锝和铼（Re）化学，并开发新的配体使用我们的扩展的一步（Al 18 F）2+方法在水溶液中的肽18 F标记。本项目的基础化学研究将促进其他人开发新的非肾综合性和双功能。99 mTc和18F诊断放射性药物以及β发射186 Re和188 Re治疗放射性药物。 我们假设，基于相对较新的{Tc 1（C 0）3}核心和Al 18FNODA-丁酸复合物的结构类似物的配体为持续的突破性研究和提高诊断准确性提供了最佳途径。在前4年的资助期间，我们建议通过使用化学方法的创新和迭代组合，多功能新型配体的有效途径和简化的动物模型来继续测试这些假设和衍生假设。同时，在第1-5年期间，这些研究的方向和新假设的产生将由我们的动物结果、在正常人受试者和肾功能降低的受试者中比较新示踪剂与131 I-OIH的结果以及在肾功能受损和疑似梗阻的受试者中比较新示踪剂与99 mTc-MAG 3的结果来指导。

Abstract of Research Plan: Our primary objective is to develop technetium (99mTc) and fluorine ('*F) renal tracers with a clearance in humans at least equal to that of the clinical gold standard, ^'l or//zo-iodohippuran ('^'l-OIH) and approaching the clearance of para-aminohippurate (PAH). Such agents should replace, the current best tracer, 99mTc Tcinercaptoacetyltriglycine (99mTc-MAGS). As detailed in this submission, we have made excellent progress in spite of the challenges posed by the disruption of the worldwide supply of iTiolybdenum-99 (the parent isotope of 99mTc) due to a temporary shutdown of aging reactors. To address a future shortage of 99mTc and to take advantage of the inherently better resolution of PET and the widespread availability of PET scanners, we are extending our original specific aims to use innovative chemistry and ligand design to develop renal tracers labeled with 18F as well as 99mTc. Our secondary objective, which will be achieved in the process of accomplishing our first objective, is to enhance the understanding of technetium and rhenium (Re) chemistry and to develop novel ligands using our extension of the one-step (Al18F)2+ method for 18F labeling of peptides in aqueous solution. The basic chemistry research in this project will facilitate the development by others of new non-renal integrated and bifunctional. 99mTc and 18F diagnostic radiopharmaceuticals as well as beta-emitting 186Re and 188Re e therapeutic radiopharmaceuticals. We hypothesize that ligands based on the relatively new {Tc1(C0)3} core and structural analogues of the Al18FNODA-butyric acid complex offer the best avenue for continued breakthrough research and enhanced diagnostic accuracy. During the first 4 years of funding, we propose to continue to test these hypotheses and derivative hypotheses by using an innovative and iterative combination of chemical methods, efficient routes to versatile novel ligands, and streamlined animal models. Simultaneously, throughout years 1-5, the direction of these studies and generation of new hypotheses will be guided by our animal results, by results comparing new tracers with 131I-OIH in both normal human subjects and those with reduced renal function, and by results comparing new tracers with 99mTc-MAG3 in subjects with impaired renal function and suspected obstruction.