Kim Young-Seung, He Zhengjie, Hsieh Wen-Yuan, Liu Shuang
Department of Industrial and Physical Pharmaceuticals, Division of Nuclear Pharmacy, Purdue University, 575 Stadium Drive, West Lafayette, Indiana 147907-205, USA.
Bioconjug Chem. 2006 Mar-Apr;17(2):473-84. doi: 10.1021/bc0502715.
This report describes a novel ternary ligand system composed of a phenylhydrazine, a crown ether-containing dithiocarbamate (DTC), and a PNP-type bisphosphine (PNP). The combination of three different ligands with (99m)Tc results in cationic (99m)Tc-diazenido complexes, [(99m)Tc(NNAr)(DTC)(PNP)]+, with potential radiopharmaceuticals for heart imaging. Synthesis of cationic (99m)Tc-diazenido complexes can be accomplished in two steps. For example, the reaction of phenylhydrazine with (99m)TcO4- at 100 degrees C in the presence of excess stannous chloride and 1,2-diaminopropane-N,N,N',N'-tetraacetic acid (PDTA) results in the [(99m)Tc(NNPh)(PDTA)n] intermediate, which then reacts with sodium N-(dithiocarbamato)-2-aminomethyl-15-Crown-5 (L4) and N,N-bis[2-(bis(3-ethoxypropyl)phosphino)ethyl]ethoxyethylamine (PNP6) at 100 degrees C for 15 min to give the complex, [(99m)Tc(NNPh)(L4)(PNP6)]+ in high yield (>90%). Cationic complexes [(99m)Tc(NNPh)(DTC)(PNP)]+ are stable for > or = 6 h. Their composition was determined to be 1:1:1:1 for Tc:NNPh:DTC:PNP using the mixed-ligand experiments on the tracer ((99m)Tc) level and was further confirmed by the ESI-MS spectral data of a model compound [Re(NNPh)(L4)(L6)]+. It was found that both DTCs and bisphosphines have a significant impact on the lipophilicity of their cationic (99m)Tc-diazenido complexes. Results from a (99m)Tc-labeling efficiency experiment showed that 4-hydrazinobenzoic acid (HYBA) might be useful as a bifunctional coupling agent for (99m)Tc-labeling of small biomolecules. However, the (99m)Tc-labeling efficiency of HYBA is much lower than that of 6-hydrazinonicotinic acid (HYNIC) with tricine and trisodium triphenylphosphine-3,3',3''-trisulfonate (TPPTS) as coligands.
本报告描述了一种由苯肼、含冠醚的二硫代氨基甲酸盐（DTC）和PNP型双膦（PNP）组成的新型三元配体体系。三种不同配体与（99m）Tc结合形成阳离子（99m）Tc-重氮络合物，即[（99m）Tc（NNAr）（DTC）（PNP）]+，有望成为用于心脏成像的放射性药物。阳离子（99m）Tc-重氮络合物的合成可分两步完成。例如，苯肼与（99m）TcO4-在100℃下，在过量氯化亚锡和1,2-二氨基丙烷-N,N,N',N'-四乙酸（PDTA）存在下反应，生成[（99m）Tc（NNPh）（PDTA）n]中间体，然后该中间体与N-（二硫代氨基甲酰基）-2-氨甲基-15-冠-5钠（L4）和N,N-双[2-（双（3-乙氧基丙基）膦基）乙基]乙氧基乙胺（PNP6）在100℃下反应15分钟，以高产率（>90%）得到络合物[（99m）Tc（NNPh）（L4）（PNP6）]+。阳离子络合物[（99m）Tc（NNPh）（DTC）（PNP）]+稳定时间≥6小时。利用示踪剂（99m）Tc水平的混合配体实验确定其组成为Tc:NNPh:DTC:PNP = 1:1:1:1，并通过模型化合物[Re（NNPh）（L4）（L6）]+的电喷雾质谱数据进一步证实。研究发现，DTC和双膦对其阳离子（99m）Tc-重氮络合物的亲脂性都有显著影响。一项（99m）Tc标记效率实验结果表明，4-肼基苯甲酸（HYBA）可能作为一种双功能偶联剂用于小分子生物分子的（99m）Tc标记。然而，以tricine和三苯基膦-3,3',3''-三磺酸钠（TPPTS）作为共配体时，HYBA的（99m）Tc标记效率远低于6-肼基烟酸（HYNIC）。
