肿瘤PET分子探针3-O-(2-^(18)F-氟乙基)-L-多巴的合成及初步生物学评价  

Synthesis and Biological Evaluation of 3-O-(2-^(18)F-fluoroethyl)-L-DOPA as A Potential PET Agent for Tumor Imaging

作　　者：马晶鑫 伍洲 姜申德[2] 王红亮[1,3] 武志芳 MA Jingxin;WU Zhou;JIANG Shende;WANG Hongliang;WU Zhifang(Department of Nuclear Medicine,First Hospital of Phanxi Medical University,Taiyuan 030001,China;School of Pharrrzaceutical Science and Technology,Tianjin University,Tianjin 300072,China;Molecular Imaging Precision Medical Collaborative Innovation Center,Shanxi Medical University,Taiyuan 030001,China)

机构地区：[1]山西医科大学第一医院核医学科,山西太原030001 [2]天津大学药物科学与技术学院,天津300072 [3]山西省分子影像精准诊疗协同创新中心,山西太原030001

出　　处：《同位素》2018年第5期310-317,共8页Journal of Isotopes

基　　金：2014年度山西省高校科技创新项目(2014134);国家自然科学基金项目(81471695;81571716);山西省科技厅基础条件平台建设项目(2015091017)

摘　　要：正电子类氨基酸显像剂是^(18)F-氟代脱氧葡萄糖(^(18)F-Fluorodeoxyglucose,^(18)F-FDG)在临床肿瘤PET显像应用中的重要补充。针对6-^(18)F-氟-L-多巴(^(18)F-FDOPA)前体制备及标记过程的复杂性,本研究设计合成了一种新型^(18)F标记的氨基酸类肿瘤PET显像剂3-O-(2-^(18)F-氟乙基)-L-多巴(3-O-(2-^(18)Ffluoroethyl-L-DOPA,^(18)F-FEDOPA),并对其内生物分布及肿瘤PET显像进行了评价。以L-多巴(LDOPA)为原料经多步反应合成标记前体化合物N-叔丁氧羰基-(3-O-甲苯磺酸酯乙基-4-O-叔丁氧羰基)-L-多巴甲酯,通过^(18)F亲核取代反应实现放射性标记,经半制备高效液相色谱纯化、盐酸水解、NaOH中和后得到^(18)F-FEDOPA注射液。放化合成时间为90min,放化产率(33±6)%(n=10,衰减校正),放射性比活度为55GBq/μmol,放化纯度>99%,4h后测定放化纯度>95%,稳定性良好。小鼠体内生物分布表明,^(18)F-FEDOPA主要经肾脏代谢,心脏和脑组织摄取值较低,骨骼摄取随时间无明显变化。microPET/CT显像显示,^(18)F-FEDOPA在H22和S180肿瘤组织有明显摄取;与^(18)F-FDG相比,^(18)FFEDOPA在注射60min时肿瘤与心(或脑)的比值高。因此,^(18)F-FEDOPA有望成为一种新型氨基酸代谢类肿瘤PET显像剂。As a complementary category to ^（18）F-2-fluoro-2-deoxy-D-glucose（^（18）F-FDG）,radiolabeled amino acids have been successfully employed for tumor imaging.To overcome the limitations of preparation of ^（18）F-FDOPA,we had designed and synthesized a new^（18）F-radiolabeled amino acid tracer 3-O-（2-^（18）F-fluoroethyl）-L-DOPA（^（18）F-FEDOPA）.Briefly,^（18）F-FEDOPA was prepared from a direct nucleophilic substitution with^（18）F using the new precusor,N-（tert-butoxycarbonyl）-3-（3-（2-（tosyloxy）ethoxy）-4-（tert-butoxycarbonyloxy））-L-DOPA methyl ester.The ^（18）F-fluorinated intermediate was purified via semi-preparative HPLC and hydrolyzed by 4 mol/L HCl.After neutralized with 2 mol/L NaOH,^（18）F-FEDOPA was obtained as injectable solution.The overall radiochemical yield of ^（18）F-FEDOPA was（33±6）%（n=10,decay corrected）within90 minutes of radiosynthesis time,and the specific activity was 55 GBq/μmol.The radiochemical purity of ^（18）F-FEDOPA（at room temperature）at 0,60,120 and 240 minutes were 99.35%,98.58%,97.98% and 97.49%,respectively,which indicated the high in vitro stability.Bio-distribution study in healthy ICR mice showed rapid clearance of ^（18）F-FEDOPA from kidneys and low uptake in most tissues especially in brain and heart.The radioactivity in brain and heart at 60 minutes post-injection of ^（18）F-FEDOPA were（1.01±0.18）%ID/g and（0.90±0.24）%ID/g,respectively.And there was no obvious uptake change in bone over the 90 minutes.microPET/CT imaging was performed on S180-H22 tumor-bearing ICR mice,which showed high accumulation of ^（18）F-FEDOPA in tumor tissue.Furthermore,the ratios of tumor to brain and tumor to heart for ^（18）F-FEDOPA（H22/brain：7.73±2.10,S180/brain：4.62±1.52,H22/heart：4.33±1.22,S180/heart：2.59±0.30）were higher than those of ^（18）F-FDG（H22/brain：2.14±0.71,S180/brain：2.14±0.71,H22/heart：1.89±0.25,S180/heart：1.56±0.30）at 60 minutes post-injection.All these

关 键 词：3-O-(2-^18F-氟乙基)-L-多巴 ^18F-标记 肿瘤 PET 生物分布 

分 类 号：TL923[核科学技术—核燃料循环与材料] R817.4[医药卫生—影像医学与核医学]