99MTC REPLACEMENTS OF 131I-HIPPURAN/STUDY AND VALIDATION

对具有生物活性的锝-99m放射性药物的需求 性能等同于或超过Iodine-131-o-orthoiodohipurate (OIH)是明确承认的。 该提案的主要目标是 描述并验证这样的代理，以便它可以用于 广泛的临床应用。 我们已经证明，Tc-99 m N，N '-双（巯基乙酰基）乙二胺（Tc-99 m DADS）及其羧酸盐 衍生物（Tc-99 m-CO2-DADS）由肾小管快速分泌 无肾潴留。 Tc-99 m-CO2-DADS的外消旋异构体与 但其潜在的临床应用是有限的，因为制备高 需要高压液相色谱法（HPLC）将其从 内异构体 我们随后开发了两种新的非常有前途的肾脏 剂. Tc-99 mHODADS具有两个异构体， 两个峰均与OIH相当; Tc-99 m巯基乙酰基三甘氨酸（Tc-99 m MAG 3） 是产生单一HPLC峰的非异构体化合物， 与OIH相比。 Tc-99 mHODADS的生物分布和排泄， Tc-99 m MAG 3和其他有前途的类似物，如Tc-99 m AlphaSCO 2DADS，将 在大鼠中与OIH和I-125碘酞酸盐进行比较，以确定 酸碱平衡、脱水、利尿、肾小管阻滞和单侧 节段性肾动脉结扎 这些复合物和参比试剂将 也可以在包括肾缺血的临床疾病模型中进行研究， 微栓塞，急性梗阻，节段性梗死，氨基糖苷类 毒性、梗阻后萎缩和肾动脉狭窄。 最后， 将在正常志愿者和患者中进行临床研究。 Tc-99 m替代OIH将消除对大多数双同位素的需求 肾脏研究（OIH和Tc-99 m DTPA）。 这将有助于改善诊断 图像，更准确的定量测量和更低的成本， 病人 它的快速肾脏排泄将导致较低的病人 辐射剂量，它可能会成为首选的Tc-99 m剂， 首次通过核心脏病学研究，特别是在儿科 患者 几乎排他的管状间隙可以允许更早地 肾小管功能障碍的检测，尤其是肾功能不全患者 移植、局部缺血或药物诱导的肾毒性。 最后这些 调查将有助于更好地了解 锝和过渡金属结构-生物分布关系 肾小管分泌中的复合物，这一认识可能导致 锝放射性药物领域的进一步发展 发展

The need for a Technetium-99m radiopharmaceutical with biological properties equivalent to or surpassing Iodine-131-o-orthoiodohippurate (OIH) is clearly recognized. The primary goal of this proposal is to characterize and validate such an agent so that it can become available for widespread clinical use. We have shown that Tc-99m N,N'-bis(mercaptoacetyl)ethylenediamine (Tc-99m DADS), and its carboxylate derivative (Tc-99m-CO2-DADS) are rapidly secreted by the renal tubules without renal retention. The exoisomer of Tc-99m-CO2-DADS is comparable to OIH but its potential clinical utility is limited because preparative high pressure liquid chromatography (HPLC) is required to separate it from the endoisomer. We have subsequently developed two new very promising renal agents. Tc-99m hydroxymethylene DADS (Tc-99m HODADS) has two isomeric peaks both comparable to OIH; Tc-99m mercaptoacetyltriglycine (Tc-99m MAG3) is a non isomeric compound producing a single HPLC peak that is also comparable to OIH. The biodistribution and excretion of Tc-99m HODADS, Tc-99m MAG3 and other promising analogs, such as Tc-99m AlphaSCO2DADS, will be compared to OIH and I-125 iothalamate in rats to determine the effect of acid-base balance, dehydration, diuresis, tubular blockade, and unilateral segmental renal artery ligation. These complexes and reference agents will also be studied in clinical disease models including renal ischemia, microembolization, acute obstruction, segmental infarction, aminoglycoside toxicity, postobstructive atrophy and renal artery stenosis. Finally, clinical studies will be conducted in normal volunteers and patients. A Tc-99m replacement for OIH will elimninate the need for most dual isotope renal studies (OIH and Tc-99m DTPA). It will result in improved diagnostic images, more accurate quantitative measurements and a lower cost to the patient. Its rapid renal excretion will result in a lower patient radiation dose and it will probably become the Tc-99m agent of choice for first transit nuclear cardiology studies particularly in pediatric patients. The nearly exclusive tubular clearance may allow earlier detection of tubular dysfunction especially in patients with renal transplants, ischemia, or drug induced nephrotoxicity. Finally, these investigations will lead to an improved understanding of the structure-biodistribution relationships of technetium and transition metal complexes in renal tubular secretion and this understanding may lead to further developments in the field of technetium radiopharmaceutical development.