中文摘要：

目的制备99^Tc^m标记的含有精氨酸-甘氨酸-天冬氨酸（Arg-Gly-Asp，RGD）序列的环肽四聚体99^Tc^m联肼尼克酰胺（HYNIC）-E{E[c（RGDfK）]2}2，评价其在整合素αvβ3表达阳性的荷人神经胶质瘤裸鼠模型的生物分布和显像。方法以HYNIC为双功能螯合剂，以三羟甲基甘氨酸（tricine）和三苯基膦三磺酸钠（TPPTS）为协同配体，采用两步法制备99^Tc^m-HYNIC—E{E[C（RGDfK）]2}2。通过体外受体竞争结合实验比较c（RGDyK）单体、HYNIC-E[c（RGDfK）]2二聚体和HYNIC—E{E[c（RGDfK）]2}2四聚体与整合素αvβ3的亲和力。对荷U87MG人神经胶质瘤裸鼠进行生物分布[以每克组织百分注射剂量率（％ID／g）表示]和显像研究。结果99^Tc^m-HYNIC-E{E[c（RGDfK）]2}2标记率〉95％，经Sep—PakC18柱纯化后放化纯〉99％。c（RGDyK）、HYNIC-E[c（RGDfK）]2和HYNIC—E{E[c（RGDfK）]2}2竞争125^I-c（RG-DyK）与整合素αvβ3的结合，其半数抑制浓度（IC50）值分别为85．9，9．5和4．5nmol／L，表明RGD环肽四聚体具有更高的整合素αvβ3亲和力。生物分布实验数据显示，99^Tc^m-HYNIC—E{E[c（RGDfK）]2}2主要经肾排泄；注射后1h，肿瘤对99^Tc^m-HYNIC—E{E[c（RGDfK）]2}2的摄取为99^Tc^m-HYNIC—E[c（RGDfK）]2的2倍，分别为（10．32±0．07）％ID／g和（5．15±0．52）％ID／g，与体外受体竞争结合实验数据相一致；注射后4h，肿瘤对99^Tc^m-HYNIC—E{E[c（RGDfK）]2}2的摄取仍达（9．35±1．35）％ID／g，表明标记物在肿瘤中的滞留时间足够长。γ显像结果显示，注射后1h肿瘤清晰可见，注射后4h显像效果更佳。结论99^Tc^m-HYNIC-E{E[c（RGDfK）]2}2具有较高的肿瘤摄取和较长的肿瘤滞留时间，可以用于整合素αvβ3表达阳性肿瘤的显像；放射性核素（如90^Y）标记的RGD环肽四聚体可用于整合素αvβ3表达阳性肿瘤的治疗。

英文摘要：

Objective Muhimeric cyclic RGD（Arg-Gly-Asp） peptides are capable of improving the integrin αvβ3-binding affinity due to the polyvalence effect. In this study, the authors prepare 99^Tc^m-la- beled cyclic RGD tetramer E{ E[ c（RGDfK）]2}2, and evaluate its biodistribution and imaging in nude mice bearing U87MG human glioma xenografts with integrinαvβ3-positive. Methods 99^Tc^m-hydrazino-nictinamide （HYNIC）-E{E[ c（RGDfK）]2}2 was prepared by two-step method, while HYNIC was chosen as bifunctional chelator, and tricine and trisodium triphenylphosphine-3,3,3 -trisulfonate （TPPTS） as coligands. The affinity of c （RGDyK） monomer, HYNIC-E [ c （RGDfK） ] 2 dimer and HYNIC-E {E[c（RGDfK）]2}2 tetramer to integrin αvβ3 was compared by in vitro competitive assay against binding of 125^I-c （RGDyK） to integrin αvβ3-positive U87MG human glioma cells. The biodistribution [ the percentage of injection dose per gram of tissue （% ID/g） ] and imaging were performed in nude mice bearing U87MG human glioma xenografts. Resuits The labehng yield of 99^Tc^m-HYNIC-E{E[c（RGDfK） ]2}2 was over 95%, and the radiochemical purity was more than 99% after purification with Sep-Pak C18 cartridge. The 50% inhibiting concentration （IC50） values of c （RGDyk）, HYNIC-E[c （RGDfK）]2 and HYNIC-E { E [ c （RGDfK） ]2 }2 were 85.9, 9.5 and 4.5 nmol/L, respectively. The result indicated that RGD tetramer possessed a significantly higher affinity to integrin αvβ3. The biodistribution data showed that 99^Tc^m-HYNIC-E { E [ c （RGDfK） ] 2 } 2 was excreted mainly through kidneys. The tumor uptake of 99^Tc^m-HYNIC-E { E[ c（RGDfK） ]2}2 was two times higher than 99^Tc^m-HYNIC-E[ C（RGDfK） ] 2, at 1 h postinjection, with the uptake of （ 10.32 ± 0.07） % ID/g and （5.15 ± 0. 52） % ID/g, respectively, which was consistent with the in vitro competitive binding data. The tumor uptake of 99^Tc^m-HYNIC-E { E[ c（RGDIK） ] 2 } 2 was still as higher as （9.35 ± 1.35 ） % ID/g at 4 h postin