新型^(68)Ga标记三七素类PSMA靶向探针的制备与评估  

Synthesis and evaluation of^(68)Ga-labeled ODAP-PSMA targeting probe

作　　者：曹祯 段小江 张景明 李源[1] 范岩[1] 杨兴 Cao Zhen;Duan Xiaojiang;Zhang Jingming;Li Yuan;Fan Yan;Yang Xing(Department of Nuclear Medicine,Peking University First Hospital,Beijing 100034,China)

机构地区：[1]北京大学第一医院核医学科,100034

出　　处：《中华核医学与分子影像杂志》2021年第10期592-596,共5页Chinese Journal of Nuclear Medicine and Molecular Imaging

基　　金：国家自然科学基金(21877004)。

摘　　要：目的制备新型^(68)Ga标记三七素类前列腺特异膜抗原(PSMA)靶向探针,并进行理化性质和体内外评估。方法采用固相合成法制备配体P151,测定其亲和性。将配体加入到^(68)GaCl3与醋酸钠混合的溶液中,95℃反应10 min,使用放射性高效液相色谱(HPLC)测定其标记率及体外稳定性。评估^(68)Ga-P151的脂水分配系数(log P),并进行细胞摄取实验。对正常昆明(KM)小鼠进行体内生物分布测定;对前列腺癌22Rv1荷瘤裸鼠注射^(68)Ga-P151后进行microPET显像,并与^(68)Ga-PSMA 617进行对比。2组间比较采用两独立样本t检验。结果成功合成目标配体P151,其抑制常数Ki为0.58 nmol/L,标记率和放化纯均≥95%;37℃放置2 h后,^(68)Ga-P151在生理盐水和人血清白蛋白(HSA)溶液中的放化纯仍≥95%,表明其体外稳定性好;^(68)Ga-P151的脂水分配系数(log P)为-2.65±0.17,表明其亲水性较好。注射^(68)Ga-P151后60 min,前列腺癌LNCaP细胞的总摄取值为(0.83±0.04)百分注射活度(%IA)/105个细胞,并可被PSMA抑制剂(ZJ-43)所抑制。正常小鼠体内生物分布显示^(68)Ga-P151主要经肾脏排泄出体外,在其他组织中摄取较低;荷瘤裸鼠microPET显像显示,^(68)Ga-P151与^(68)Ga-PSMA 617的最大标准摄取值(SUVmax:0.79±0.23和0.54±0.05;t=2.12)、肿瘤/肾脏比值(2.04±0.65和1.88±0.33;t=0.44)、肿瘤/肌肉比值(12.83±5.18和6.95±1.63;t=2.17)差异均无统计学意义(均P>0.05)。结论^(68)Ga-P151制备简单、标记率高、生物分布理想,可对PSMA阳性肿瘤显像,其显像效果与^(68)Ga-PSMA 617相当,有望应用于前列腺癌的诊断。Objective To synthesize a ^(68)Ga-labeled oxalyldiaminopropionic acid(ODAP)-urea based prostate specific membrane antigen(PSMA)targeting probe,and evaluate its properties in vitro and in vivo.Methods Ligand P151 was synthesized by solid-phase synthesis and its Ki value was determined.The ligand P151 was added into the mixture of ^(68)GaCl3 and NaOAc solution and was reacted at 95℃for 10 min.The labeling yield and in vitro stability of ^(68)Ga-P151 were determined by high performance liquid chromatography(HPLC).The lipid-water partition coefficient(log P)and cell binding ability were determined.The biodistribution of ^(68)Ga-P151 in normal KM mice was determined.MicroPET imaging of ^(68)Ga-P151 was carried out in prostate cancer 22Rv1 tumor-bearing mice and compared with ^(68)Ga-PSMA 617.Independent sample t test was used to analyze the data.Results P151 was successfully synthesized with the Ki of 0.58 nmol/L,the labeling yield more than 95%and the radiochemical purity more than 95%.After placement in saline or human serum albumin(HSA)solution at 37℃for 2 h,the radiochemical purity of ^(68)Ga-P151 was still more than 95%,indicating a good stability in vitro.The lipid-water partition coefficient(log P)of ^(68)Ga-P151 was-2.65±0.17,indicating a good hydrophilicity.^(68)Ga-P151 specifically bound to PSMA in prostate cancer LNCaP cells with the uptake value of(0.83±0.04)percentage injection activity(%IA)/105 cells.Biodistribution of normal mice showed that ^(68)Ga-P151 was mainly excreted through kidneys and other organs showed low uptake.MicroPET imaging of tumor-bearing mice showed the maximum standardized uptake value(SUVmax:0.79±0.23 vs 0.54±0.05;t=2.12),tumor/kidney ratio(2.04±0.65 vs 1.88±0.33;t=0.44)and tumor/muscle ratio(12.83±5.18 vs 6.95±1.63;t=2.17)between ^(68)Ga-P151 and ^(68)Ga-PSMA 617 were not significantly different(all P>0.05).Conclusions ^(68)Ga-P151 can be prepared simply and labeled in high yield and show improved pharmacokinetic properties in vivo.The imaging of ^(68)Ga-P151 on PSMA p

关 键 词：氨基酸类 二氨基 同位素标记 镓放射性同位素 前列腺特异膜抗原 正电子发射断层显像术 肿瘤细胞 培养的 小鼠 裸 

分 类 号：R737.25[医药卫生—肿瘤] R730.44[医药卫生—临床医学]