Development of Tc-99m Renal Tubular Tracers

研究计划摘要：我们的主要目标是开发~(99m)Tc和~(*F)F肾示踪剂 人体清除量至少等于临床黄金标准，^‘L或//偶氮碘马尿酸(’^‘L-OIH)和 接近清除对氨基马尿酸(PAH)。这些试剂应该取代目前最好的示踪剂99mTC-乙酰甘氨酸(99mTC-MAGS)。如本材料所述，尽管由于老化反应堆的临时关闭而中断了99mTc的母体同位素iTiolybdenum-99的全球供应，但我们仍取得了极大的进展。为了解决未来99mTc的短缺问题，并利用PET固有的更好的分辨率和PET扫描仪的广泛应用，我们正在扩展我们最初的特定目标，使用创新的化学和配体设计来开发标记有18F和99mTc的肾脏示踪剂。 我们在达到第一个目标的过程中会达到的第二个目标，是加强 通过对水溶液中18F标记多肽的一步法(Al18F)2+方法的扩展，了解锶和Re(Re)化学并开发新的配体。本项目的基础化学研究将促进其他非肾脏一体化和双功能新型药物的开发。99mTc和18F诊断性放射性药物以及贝塔发射的186Re和188Re治疗性放射性药物。 我们假设，基于相对较新的{Tc1(C0)3}核心和Al18FNoda-丁酸络合物的结构类似物的配体为继续突破性研究和提高诊断准确性提供了最佳途径。在最初4年的资助中，我们建议继续通过创新和迭代的化学方法组合、高效的途径来实现多用途的新型配体和简化的动物模型来检验这些假说和衍生假说。同时，在1-5年期间，这些研究的方向和新假说的产生将以我们的动物结果为指导，通过在正常人和肾功能减退者中将新示踪剂与131I-OIH进行比较的结果，以及在肾功能受损和可疑梗阻的受试者中将新示踪剂与99mTC-MAG3进行比较的结果。

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.