不同电荷肿瘤乏氧显像剂的合成及生物分布

电荷是药物分子的重要性质,可以影响其在体内的生物学行为。为了研究不同电性质的肿瘤乏氧显像剂在体内的生物分布行为,合成了3种带有不同电荷的肿瘤乏氧显像剂(S)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酸甲酯(NI-Y-M)、(S)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酸(NI-Y)和(S)-N-(3-胺丙基)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酰胺(NI-Y-A),并进行了131I标记。3种化合物的标记率均大于95%,体外稳定性好。纸上电泳结果表明,在生理条件下,131I]NI-Y-M为中性分子,131I]NI-Y和131I]NI-Y-A则分别呈现负电和正电的电性质。从荷S180肉瘤小鼠体内分布结果发现:3种标记物在肿瘤组织呈现出快摄取慢清除的趋势,并且在肿瘤中的放射性活度明显高于肌肉和心、脑、脾等组织;随着时间的延长,肿瘤的相对摄取率提高;4h时,动物肿瘤与肌肉、肿瘤与血液放射性摄取的比值数据显示,带正电荷的标记物131I]NI-Y-A是最优的肿瘤乏氧显像剂。

Preparation and Biodistribution of Tumor Hypoxia Imaging Agents With Different Charges

The charge is an important characteristic of a drug molecule.The overall charge on a drug affects its pharmacological properties in vivo.In this study,(S)-methyl 3-(4-hydroxyphenyl)-2-(3-(2-nitro-1H-imidazol-1-yl)propanamido)propanoate(NI-Y-M),(S)-3-(4-hydroxyphenyl)-2-(3-(2-nitro-1H-imidazol-1-yl)propanamido) propanoic acid(NI-Y) and(S)-N-(3-aminopropyl)-3-(4-hydroxyphenyl)-2-(3-(2-nitro-1H-imidazol-1-yl)propanamido)propanamide(NI-Y-A) were synthesized and radioiodinated with 131I.All the radioiodinated compounds are obtained in >95% yield determined by HPLC and stable at room temperature for 24 h in vitro.The paper electrophoresis results indicate that the compounds formed are different in charge,NI-Y-M,NI-Y,and NI-Y-A are neutral,negative and positive,respectively.The biodistribution results in mice bearing S180 tumor demonstrate that all of the NI-Y-M,NI-Y and NI-Y-A accumulate in tumor fast and slowly clear from it.The uptakes in tumor are higher than those in muscle,heart,brain and spleen.The tumor-to-tissue ratios increase along with time.At 4 h post injection,the uptake ratios of tumor-to-muscle and tumor-to-blood indicate that among them the positively charged NI-Y-A is the best hypoxia agent.