不同电荷肿瘤乏氧显像剂的合成及生物分布

Preparation and Biodistribution of Tumor Hypoxia Imaging Agents With Different Charges

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。

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-1 H-imidazol-l-yl） propanamido） propanoate （NI-Y-M）, （ S）-3- （4-hydroxyphenyl） -2- （ 3- （ 2-nitro-1 H-imidazol-1-yl ） propanamido） propanoic acid （NI-Y） and （S） -N-（ 3-aminopropyl ） -3- （ 4-hydroxyphenyl ）-2-（ 3-（ 2-nitro-1 H-imidazol-l-yl ） propanamido ） propanamide （NI-Y-A） were synthesized and radioiodinated with ^131 I. 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, [^1311]NI-Y-M, [^131 I]NI-Y, and [^1311] NI-Y-A are neutral, negative andpositive, respectively. The biodistribution results in mice bearing S180 tumor demonstrate that all of the [^131 I]NI-Y-M, [^131 I]NI-Y and [^131 I]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 up- take ratios of tumor-to-muscle and tumor-to-blood indicate that among them the positively charged [^1311]NI-Y-A is the best hypoxia agent.