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

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。

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

As a complementary category to¹⁸F-2-fluoro-2-deoxy-D-glucose (¹⁸F-FDG), radiolabeled amino acids have been successfully employed for tumor imaging. To overcome the limitations of preparation of¹⁸F-FDOPA, we had designed and synthesized a new¹⁸F-radiolabeled amino acid tracer 3-O-(2-¹⁸F-fluoroethyl)-L-DOPA (¹⁸F-FEDOPA). Briefly,¹⁸F-FEDOPA was prepared from a direct nucleophilic substitution with¹⁸F using the new precusor, N-(tert-butoxycarbonyl)-3-(3-(2-(tosyloxy)ethoxy)-4-(tert-butoxycarbonyloxy))-L-DOPA methyl ester. The¹⁸F-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 of¹⁸F-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 of¹⁸F-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 of¹⁸F-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 of¹⁸F-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 of¹⁸F-FEDOPA in tumor tissue. Furthermore, the ratios of tumor to brain and tumor to heart for¹⁸F-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 of¹⁸F-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 that¹⁸F-FEDOPA would be a potential amino acid tracer for tumors PET imaging.