^(11)C左旋间羟基麻黄素制备方法的优化及改进

Optimization and improvement of production of(-)-[^(11)C]meta-Hydroxyephedrine

目的:优化及改进交感神经受体显像剂11C标记左旋间羟基麻黄素((-)-[11C]HED)的放射化学合成反应条件和分离纯化方法。方法:利用14N(p,α)11C核反应生产[11C]-CO2,使用TRACERlab FXc碳多功能化学合成器在线制备甲基化试剂11C-三氟甲基磺酰基甲烷([11C]-CH3OTf)。将前体间羟胺的乙腈溶液降温至0℃捕获[11C]-CH3OTf后,加热进行甲基化反应。利用半制备C-18反相色谱柱,以生理盐水/乙醇95/5(v∶v)作为半制备色谱流动相分离纯化反应产物,切峰、除菌后得到(-)-[11C]HED注射液。采用单因素分析和正交实验设计法,选择放化反应温度(A)、时间(B)、前体用量(C)为因素各取3水平,按L(934)正交表进行实验。结果:放化反应温度为主要因素,前体用量及反应时间为次要因素。结合正交实验结果和纯化实际情况,确定最佳工艺条件为A3B1C3,即反应温度70℃、前体用量0.2 mg、反应时间40 s。验证实验结果显示自[11C]-CO2轰击结束计时,(-)-[11C]HED制备耗时约25 min。产物的校正产率(校正至[11C]CH3I的活度)为(49.1±5.1)%(43.2%~60.9%()n=50),放射化学纯度>99%(n=50),产物放射性比活度(24.4±2.2)(19.4~27.8)GBq·μmol-(1n=50)。细菌、内毒素检测结果均为阴性。结论:制备方法的优化及改进可使自动化制备(-)-[11C]HED过程高效、便捷。

Objective：To optimize methylated conditions and improve purification protocol of （-）-[11C]meta-Hydroxyephedrine （（-）-[11C] HED） synthesis, as a receptor of sympathetic nervous system, to get relatively high labeling yield. Methods： [11C]-CO2 was produced via 14N （p, α） 11C nuclear reaction. 11C-Methyl Triflate （[11C]-CH3OTf）, served as the [11C]methylation reagent, was obtained online by GE TRACERlab FXc synthesis module, and bubbled into reactor at 0℃until maximum radioactivity was accumulated. （-）-[11C]HED was synthesized by direct N-methylation of metaraminol with [11C]-CH3OTf. The product was purified by semi-preparative reversed-phase HPLC with the eluent saline/ethanol 95/5 （v：v）. Single factor analysis and orthogonal experimental design were applied to investigate the optimized methylated synthesis conditions with L9 （34） orthogonal test. Results：The reaction temperature was the main process factor, and the amount of precursor was the secondary factor. In consideration of the situation of orthogonal experimental results and purification, the optimum condition was A3B1C3, in which the reactor was heated to 70℃to ensure 0.2 mg precursor was methylated with [11C]-CH3OTf for 40 s. The validation test results illustrated that the total synthesis time of the tracer was approximately 25 min from end-of-bombardment. The radiochemical yield was（49.1±5.1）%（43.2%～60.9%） （n=50, corrected to [11C]CH3I） . The radiochemical purity of the product was up to 99%（n=50）. The specific activity was（24.4±2.2） （19.4～27.8） GBq·μmol-1 （n=50） at end of synthesis. Conclusion：Reaction temperature, amounts of precursor and reaction time are the most important conditions for the methylated reaction. The automatic radiosynthesis procedure of （-）-[11C]HED with relatively high radiochemical yield is convenient and efficient.