Vanbilloen H P, Dezutter N A, Cleynhens B J, Verbruggen A M
Department of Nuclear Medicine, U.Z. Gasthuisberg, Leuven, Belgium.
Eur J Nucl Med. 1997 Nov;24(11):1374-9. doi: 10.1007/s002590050163.
Substitution of the oxidation-sensitive thiol function of mercaptoacetyltriglycine (MAG3) by a hydroxyl group yields a tetraligand (hydroxyacetyltriglycine or HAG3) which is almost insensitive to oxidation and has the advantage over MAG3 that it can be stored safely without protection of the alcohol function. We found that deprotected HAG3 could be directly labelled at alkaline pH (pH>/=11.5) and room temperature in high yield (>95%). Results of electrophoresis experiments suggested a comparable structure for 99mTc-HAG3 and 99mTc-MAG3, namely binding of an oxotechnetium(V)core via three deprotonated amides and a deprotonated hydroxyl group. Biodistribution studies in mice at 10 min and 30 min p.i. showed a slightly higher urinary excretion, a faster renal transit and a significantly lower hepatobiliary handling for 99mTc-HAG3 than for 99mTc-MAG3. In a baboon, the 1-h plasma clearance of 99mTc-HAG3 was clearly higher than that of 99mTc-MAG3. Its plasma protein binding was in the same order as that of Hippuran and much lower than that of 99mTc-MAG3. Evaluation in a human volunteer confirmed the favourable biological characteristics of 99mTc-HAG3, namely a rapid renal excretion, a high 1-h plasma clearance and a negligible hepatobiliary handling. The results indicate that 99mTc-HAG3 may be an easy-to-prepare and practical substitute for 99mTc-MAG3 with improved renal excretion characteristics.
将巯基乙酰三甘氨酸（MAG3）对氧化敏感的硫醇官能团用羟基取代，可得到一种四齿配体（羟基乙酰三甘氨酸或HAG3），它对氧化几乎不敏感，与MAG3相比具有如下优势：无需对醇官能团进行保护即可安全储存。我们发现，脱保护的HAG3在碱性pH值（pH≥11.5）和室温下可直接进行标记，产率很高（>95%）。电泳实验结果表明，99mTc-HAG3和99mTc-MAG3具有类似的结构，即通过三个去质子化的酰胺和一个去质子化的羟基与一个锝（V）氧基核心结合。注射后10分钟和30分钟对小鼠进行的生物分布研究表明，与99mTc-MAG3相比，99mTc-HAG3的尿排泄略高、肾转运更快且肝胆摄取显著更低。在一只狒狒身上，99mTc-HAG3的1小时血浆清除率明显高于99mTc-MAG3。其血浆蛋白结合情况与马尿酸的血浆蛋白结合情况处于同一水平，且远低于99mTc-MAG3。在一名人类志愿者身上进行的评估证实了99mTc-HAG3具有良好的生物学特性，即肾排泄迅速、1小时血浆清除率高且肝胆摄取可忽略不计。结果表明，99mTc-HAG3可能是一种易于制备且实用的99mTc-MAG3替代品，其肾排泄特性有所改善。
