同位素 ›› 2018, Vol. 31 ›› Issue (5): 310-317.DOI: 10.7538/tws.2017.youxian.070

• PET正电子放射性药物专辑 • 上一篇    下一篇

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

马晶鑫1;伍洲2;姜申德2;王红亮1,3;武志芳1,3   

  1. 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
  • 出版日期:2018-10-20 发布日期:2020-08-14

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

MA Jingxin1;WU Zhou2;JIANG Shende2;WANG Hongliang1,3;WU Zhifang1,3   

  1. 1.Department of Nuclear Medicine, First Hospital of Shanxi Medical University, Taiyuan 030001, China; 2.School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China; 3.Molecular Imaging Precision Medical Collaborative Innovation Center, Shanxi Medical University, Taiyuan 030001, China
  • Online:2018-10-20 Published:2020-08-14

摘要:

正电子类氨基酸显像剂是18F-氟代脱氧葡萄糖(18F-Fluorodeoxyglucose, 18F-FDG)在临床肿瘤PET显像应用中的重要补充。针对6-18F-氟-L-多巴(18F-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18F-标记的氨基酸类肿瘤PET显像剂3-O-(2-18F-氟乙基)-L-多巴(3-O-(2-18F-fluoroethyl-L-DOPA, 18F-FEDOPA),并对其内生物分布及肿瘤PET显像进行了评价。以L-多巴(L-DOPA)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18F-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18F-FEDOPA注射液。放化合成时间为90 min,放化产率(33±6)%(n=10,衰减校正),放射性比活度为55 GBq/μmol,放化纯度>99%,4 h后测定放化纯度>95%,稳定性良好。小鼠体内生物分布表明,18F-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,18F-FEDOPA在H22和S180肿瘤组织有明显摄取;与18F-FDG相比,18F-FEDOPA在注射60 min时肿瘤与心(或脑)的比值高。因此,18F-FEDOPA有望成为一种新型氨基酸代谢类肿瘤PET显像剂。

关键词: 3-O-(2- 18F-氟乙基)-L-多巴, 18F-标记, 肿瘤, PET, 生物分布

Abstract:

As a complementary category to 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG), radiolabeled amino acids have been successfully employed for tumor imaging. To overcome the limitations of preparation of 18F-FDOPA, we had designed and synthesized a new 18F-radiolabeled amino acid tracer 3-O-(2-18F-fluoroethyl)-L-DOPA (18F-FEDOPA). Briefly, 18F-FEDOPA was prepared from a direct nucleophilic substitution with 18F using the new precusor, N-(tert-butoxycarbonyl)-3-(3-(2-(tosyloxy)ethoxy)-4-(tert-butoxycarbonyloxy))-L-DOPA methyl ester. The 18F-fluorinated intermediate was purified via semi-preparative HPLC and hydrolyzed by 4 mol/L HCl. After neutralized with 2 mol/L NaOH, 18F-FEDOPA was obtained as injectable solution. The overall radiochemical yield of 18F-FEDOPA was (33±6)% (n=10, decay corrected) within 90 minutes of radiosynthesis time, and the specific activity was 55 GBq/μmol. The radiochemical purity of 18F-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 18F-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 18F-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 18F-FEDOPA in tumor tissue. Furthermore, the ratios of tumor to brain and tumor to heart for 18F-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 18F-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 results indicated that 18F-FEDOPA would be a potential amino acid tracer for tumors PET imaging.

Key words: 3-O-(2-18F-fluoroethyl)-L-DOPA, 18F-labelling, tumor, positron emission tomography (PET), bio-distribution