多巴胺受体显像剂 18F-Fethypride的合成、 放射性标记及生物分布

以香草酸甲酯为原料, 经过7步反应合成了前体化合物(S)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯, 采用NMR和HRMS对其进行了表征; 通过¹⁸F标记合成了新型高亲和力的多巴胺受体显像剂¹⁸F-(S)-N-{(1-乙基2-吡咯烷基)甲基}-3-(3-氟丙基)-4,5-二甲氧基苯甲酰胺(¹⁸F-Fethypride). 该显像剂的合成时间为35 min, 放化产率为(36.8±1.4)%(n=6), 放化纯度经HPLC法检测为99%, TLC法检测为100%, 无菌实验、 鲎试剂检测、 K2.2.2含量检测和急性毒性实验均合格. 纹状体/小脑(Str/Cer)比值90 min达到最高(10.68±0.35), 可作为多巴胺受体显像剂用于诊断神经系统疾病.

Synthesis,Label and Biodistribution of 18F-Fethypride for Dopamine Receptor Imaging†

Dopamine is one of important neurotransmitters in the brain, many diseases of the nervous system is closely related to it. Developing the dopamine receptor imaging agents of strong specificity and high affinity is a hot topic in the field of molecular nuclear medicine. The precursor(S)-3-[5-{(1-ethylpyrrolidin-2-yl) methylcarbamoyly}-2,3-dimethoxy phenyl] propyl-4-methyl benzemide was synthetized with vanillic acid methyl ester through seven steps, then radioactive compound ¹⁸F-(S)-N-{(1-ethylpyrrolidin-2-yl)methyl}-3-(3-fluropropyl)-4, 5-dimethoxy benzamide(¹⁸F-Fethypride) was radiolabeled by ¹⁸F through nucleophilic substitution reaction. Synthesis time was 35 min, radiochemical yield rate was (36.8±1.4)%, radiochemical purity of HPLC was 99%, radiochemical purity of TLC was 100%. Sterility test limulus reagent test K2.2.2 content detection and acute toxicity test were all qualified. Biodistribution test showed that ¹⁸F-Fethypride was metabolized through the liver, excreted through the renal, radioactivity gradually decreased with the extension of time. In brain tissue, radioactivity were mainly distributed in striatum, then in hippocampus, hypothalamus and cerebellum were lower. Striatum/cerebellum(Str/Cer) increased gradually, reached the highest at 90 min(10.68±0.35). The results showed that ¹⁸F-Fethypride was suit for the diagnosis of the nervous system diseases as dopamine receptor imaging agent.