Routine production of [(18)f]flumazenil from iodonium tosylate using a sample pretreatment method: a 2.5-year production report.
OBJECTIVE
[(18)F]Flumazenil, which has the advantage of a longer half-life than [(11)C]flumazenil, is well known for determining of the central benzodiazepine receptor concentrations. However, [(18)F]flumazenil has not been widely used because fluctuating and relatively low yields render automatic production insufficient for routine and multicenter clinical trials. Here, we describe the results of a 2.5-year production study of [(18)F]flumazenil using an iodonium tosylate precursor, which allowed us to overcome the limitations of low and fluctuating radiochemical yields.


METHODS
We developed a clinically applicable production system by modifying a commercial synthesizer for the reliable and reproducible production of [(18)F]flumazenil for routine clinical studies. [(18)F]Flumazenil was prepared at 150 °C for 5 min in the presence of 4-methylphenyl-mazenil iodonium tosylate (4 mg), a radical scavenger (TEMPO, 1 mg), and [(18)F]KF/kryptofix 2.2.2 complex in N,N-dimethylformamide (1 ml). In the purification step, the final mixture was pretreated using different cartridges before performing high-performance liquid chromatography (HPLC) separation. Finally, we measured the radiochemical yield and performed quality-control assays on 94 batches.


RESULTS
After carrying out additional purification before HPLC separation using a C18 plus Sep-Pak cartridge, the radiochemical yield of [(18)F]flumazenil increased from 34.4 ± 9.7 % (without the pretreatment, n = 24) to 53.4 ± 9.0 % (n = 94), and the lifetime of the semi-preparative column was five times that of the column without the C18 plus Sep-Pak cartridge. The mean-specific activity of [(18)F]flumazenil was 572 ± 116 GBq/μmol at the end of synthesis, and the radiochemical purity was more than 99 %, as determined by analytical HPLC and radio-TLC. [(18)F]Flumazenil prepared using this method satisfied all quality-control test standards and was highly stable for up to 6 h after preparation.


CONCLUSIONS
The results of the 2.5-year production study using an iodonium tosylate precursor indicate that [(18)F]flumazenil has commercial and routine clinical applicability.
Department of Nuclear Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 300 Gumidong, Bundanggu, Seongnam, 463-707, Republic of Korea.
Byung Seok
BS
Moon
Jun Hyung
JH
Park
Hong Jin
HJ
Lee
Byung Chul
BC
Lee
Sang Eun
SE
Kim
D002851:Chromatography, High Pressure Liquid; D005442:Flumazenil / Q000138:chemical synthesis* / Q000737:chemistry; D005462:Fluorine Radioisotopes / Q000737:chemistry*; D007202:Indicators and Reagents; D009861:Onium Compounds / Q000737:chemistry*; D011786:Quality Control; D011854:Radiochemistry / Q000379:methods*; D014105:Tosyl Compounds / Q000737:chemistry*
D005462:Fluorine Radioisotopes; D007202:Indicators and Reagents; D009861:Onium Compounds; D014105:Tosyl Compounds; D005442:Flumazenil