18F-DPA-714的自动化合成、质量控制及其在脑外伤模型中的初步研究

Automated Synthesis, Quality Control, and Preliminary Application of 18F-DPA-714 in a Traumatic Brain Injury Model

  • 摘要: 为建立18F-DPA-714的全自动合成工艺、验证其质量,使用8周龄雄性C57BL/6小鼠,建立控制性皮质撞击(controlled cortical impact,CCI)小鼠模型并对其进行初步的炎症显像验证。本研究采用日本住友氟多功能药物合成模块(CFN),以pre-DPA-714为前体,经亲核取代反应合成18F-DPA-714,并研究最佳反应条件。经高效液相色谱(HPLC)分离纯化(流动相:45%乙腈/0.1%TFA),C18固相萃取柱富集,最终无菌过滤制备注射液。依据相关规范,对三批产品的关键质量指标进行评估,包括放化产率、放化纯度、pH、乙醇与K2.2.2残留、无菌及细菌内毒素检测。结果显示18F-DPA-714的最佳合成条件为:反应温度100 ℃,反应时间10 min,前体用量2 mg。包括从18F离子干燥到制成最终产品的总时间约45 min,未校正放化产率为 (42.5±3.2)%(n=30),放化纯度 >99%。终产品为无色澄明溶液,pH 5.5~7.0;残留乙腈<0.04%,K2.2.2<50 μg/mL;乙醇含量<10%,比活度为80~102 GBq/μmol;无菌及细菌内毒素检测均符合《中国药典》规定。该研究中对脑外伤模型的初步炎症显像验证,进一步证实了18F-DPA-714在神经炎症评估方面的潜力。本研究采用的制备工艺由已有自动化合成模块(住友CFN)完成、重复性好(n≥30),产品质量稳定可靠,可满足日后临床应用的质量要求。

     

    Abstract: Objective: To establish an automated synthesis process for 18F-DPA-714, validate its quality, and conduct preliminary imaging verification of inflammation in a traumatic brain injury model. Methods: Using a Sumitomo CFN fluorine multifunctional synthesis module from Japan, 18F-DPA-714 was synthesized via nucleophilic substitution with pre-DPA-714 as the precursor. After optimizing reaction conditions, the product was purified by semi-preparative High-Performance Liquid Chromatography (HPLC) with a mobile phase of 45% acetonitrile/0.1% trifluoroacetic acid (TFA), concentrated on a C18 solid-phase extraction (SPE) cartridge, and finally sterile-filtered to obtain the injectable solution. Three batches of the product underwent quality control (QC) assessments, including radiochemical yield (RCY), radiochemical purity (RCP), pH, residual solvents (acetonitrile, K2.2.2), sterility, and bacterial endotoxin levels. Results: The results indicated that the optimal synthesis conditions for 18F-DPA-714 were as follows: the reaction temperature is 100 ℃, the reaction time is 10 min, and the precursor amount is 2 mg. The total synthesis time, from the drying of 18F-fluoride to the final product, was approximately 45 min, exhibiting an uncorrected radiochemical yield of (42.5±3.2)% (n=30) and a radiochemical purity >99%. The final formulation was a clear, colorless solution (pH 5.57.0) with residual acetonitrile <0.04% and K2.2.2 <50 μg/mL, ethanol content <10%, specific activity 80-102 GBq/μmol, and it complied with the Chinese Pharmacopoeia standards for sterility and bacterial endotoxins. Preliminary inflammatory imaging validation in traumatic brain injury models in this study further confirmed the potential of 18F-DPA-714 for neuroinflammation assessment. The preparation process adopted in this work was completed using an existing automated synthesis module (Sumitomo CFN), demonstrating good reproducibility (n≥30) and stable, reliable product quality, which can meet the quality requirements for future clinical applications.

     

/

返回文章
返回