Chatterjee M, Banerjee S
Indian Institute of Chemical Biology, Calcutta, India.
Int J Rad Appl Instrum B. 1991;18(3):263-74. doi: 10.1016/0883-2897(91)90121-z.
Substituted monoanilides of nitrilotriacetic acid (NTA) have gained much popularity in recent years as an important class of ligands for technetium-99m (99mTc) radiopharmaceutical preparations used in liver imaging and function studies. We were interested in investigating the properties of the corresponding ester analogues of this important class of ligands and for this study cyclohexanol was selected as a hydroxy component, which on condensation with nitrilotriacetic acid in the presence of acetic anhydride, furnished the monoester, N-cyclohexyloxycarbonylmethyl iminodiacetic acid 4 and the corresponding diester 5. Phenol on similar condensation produced mainly the diester, N,N-di(phenyloxycarbonylmethyl) aminoacetic acid 2, with traces of the corresponding monoester 7. A reinvestigation of the well known condensation reaction of aniline with nitrilotriacetic acid revealed that in addition to the reported monoanilide, N-phenylcarbamoylmethyl imino diacetic acid 3, the corresponding dianilide 6 was also produced in appreciable amount. The ester ligands 2, 4, 5 after 99mTc chelation exhibited good in vitro and in vivo stabilities. The biodistribution characteristics of these radiolabelled esters and amides were very similar showing thereby that esterification with NTA could be an effective method for converting alcohols to 99mTc-radiopharmaceuticals without generating any unusual properties because of the ester linkage. Residual radiopharmaceutical concentration after i.v. administration of these amide and ester 99mTc chelates at 30 min in blood, urine, liver, kidney and intestine were correlated with their lipophilicities and during this correlation it was observed that in addition to lipophilicity the anionic strength of these chelates is also an important determinant in governing their biodistribution. The ester ligand 4 after 99mTc chelation showed ultrafast hepatobiliary kinetics and was therefore compared in a rabbit model with a standard hepatobiliary radiopharmaceutical 99mTc-N-(p-butylphenylcarbamoyl methyl) iminodiacetic acid (99mTc-BIDA) by gamma-camera scintigraphy to investigate the potential of the former for clinical studies.
近年来，次氮基三乙酸（NTA）的取代单酰苯胺作为一类重要的配体，在用于肝脏成像和功能研究的锝-99m（99mTc）放射性药物制剂中颇受关注。我们对研究这类重要配体的相应酯类似物的性质感兴趣，在本研究中，选择环己醇作为羟基成分，其在乙酸酐存在下与次氮基三乙酸缩合，得到单酯N-环己氧基羰基甲基亚氨基二乙酸4和相应的二酯5。苯酚在类似缩合反应中主要生成二酯N,N-二（苯氧基羰基甲基）氨基乙酸2，并伴有痕量的相应单酯7。对苯胺与次氮基三乙酸的著名缩合反应重新进行研究发现，除了已报道的单酰苯胺N-苯基氨基甲酰基甲基亚氨基二乙酸3外，还生成了相当量的相应二酰苯胺6。酯配体2、4、5与99mTc螯合后在体外和体内均表现出良好的稳定性。这些放射性标记的酯和酰胺的生物分布特征非常相似，这表明用NTA进行酯化可能是一种将醇转化为99mTc放射性药物的有效方法，且不会因酯键而产生任何异常性质。静脉注射这些酰胺和酯99mTc螯合物30分钟后，血液、尿液、肝脏、肾脏和肠道中的放射性药物残留浓度与其亲脂性相关，在此相关性研究中观察到，除亲脂性外，这些螯合物的阴离子强度也是决定其生物分布的重要因素。酯配体4与99mTc螯合后显示出超快的肝胆动力学，因此在兔模型中通过γ相机闪烁显像与标准肝胆放射性药物99mTc-N-（对丁基苯基氨基甲酰基甲基）亚氨基二乙酸（99mTc-BIDA）进行比较，以研究前者用于临床研究的潜力。
