Synthesis and Quality Control of the PET Radiotracer ¹¹C-Flumazenil

To produce the radioligand ¹¹C-flumazenil at very high quality and specific radioactivity for routinely clinical imaging, the procedures for its synthesis and purification were developed with domestic PET-CM-3H-IT-I synthesis module, and ¹¹C-CH₃I was used as methylation agent. ¹¹C-CH₃I was first synthesized by liquid phase reaction, the synthesis conditions of radiotracer ¹¹C-flumazenil were studied, which included the alkali strength, alkali equivalent, solvents, temperature and purification conditions for the product. The optimum conditions were that ¹¹C-CH₃I was bubbled through a reactor at room temperature, containing a DMF solution of 1 mg desmethylflumazenic precursor and 1 mg NaH, the reaction was conducted at 55 ℃ for 2 minutes. The reaction solution was first transferred to Semi-HPLC for purification, the mobile phase consisted of acetonitrile-acetic acid-water (30∶4∶66), the flow rate was 5.0 mL/min, then the crude product was purified by C-18 Solid-Extraction Purification(SEP), the product retained on SEP cartridge was eluted with 1 mL alcohol, the eluant was diluted with 6 mL sterile injection water, the dilute solution passed through sterile membrane to end-product. The radiochemical purity and specific radioactivity were measured by High Performance Liquid Chromatograph (HPLC) with the mobile phase of acetonitrile-acetic acid-water (30∶4∶66), and the column was ODS (250 mm×4.6 mm, 5 μm). The results showed that the total synthesis time was (26±2) minutes from ¹¹C-CO₂ to obtain ¹¹C-flumazenil injection solution, the synthesis yield of ¹¹C-flumazenil was (45±4)% (decay corrected, n=10), the radiochemical purity was over 99% at specific activity of 4.7 TBq/mmol, the radioactivity concentration was 370～550 MBq/mL. The injection solution was proved to be sterile and pyrogen free. The radiochemical yield was increased greatly by optimizing the reaction conditions, ¹¹C-flumazenil was synthesized from ¹¹C-CH₃I with domestic C-11 synthesis module, the quality and quantity of ¹¹C-flumazenil was confirmed to be suitable for clinic use.