One-step high-radiochemical-yield synthesis of [¹⁸F]FP-CIT using a protic solvent system

Abstract 

Although [¹⁸F] fluoropropylcarbomethoxyiodophenylnortropane (FP-CIT) is a promising radiopharmaceutical for dopamine transporter imaging, it has not been used for clinical studies because of low radiochemical yield. The purpose of our study was to develop a new radiochemistry method using a protic solvent system to obtain a high radiochemical yield of [¹⁸F]FP-CIT in single-step manual and automatic preparation procedures. [¹⁸F]F⁻ was trapped on a QMA Sep-Pak cartridge or PS-HCO₃ cartridge and eluted with Cs₂CO₃/K₂₂₂ buffer or TBAHCO₃, respectively, or 8 μl of TBAOH was added directly to [¹⁸F]F⁻/H₂¹⁸O solution in a reactor without using a cartridge. After drying, [¹⁸F] fluorination was performed with 2–6 mg of mesylate precursor, 100 μl of CH₃CN and 500 μl of t-BuOH at 50–120°C for 5–30 min, followed by high-performance liquid chromatography (HPLC) purification to obtain the final product. For comparison, the same procedure was performed with a tosylate precursor. Manual synthesis gave a decay-corrected radiochemical yield of 52.2±4.5%, and optimal synthesis conditions were as follows: TBAOH addition, 4 mg of precursor, 100°C and 20 min of [¹⁸F] fluorination (n=3). We obtained low radiochemical yields of [¹⁸F]FP-CIT with carbonate elution systems such as Cs₂CO₃ or TBAHCO₃. We also developed an automatic synthesis method based on manual synthesis results. In automatic production, we obtained a decay-corrected radiochemical yield of 35.8±5.2% after HPLC purification, and we did not have any synthesis failures (n=14). Here, we describe our new method for the synthesis of [¹⁸F]FP-CIT using a protic solvent system. This method gave a high radiochemical yield with high reproducibility and might enable [¹⁸F]FP-CIT to be used clinically and commercially.

Keywords: [¹⁸F]FP-CIT, Protic solvent, Nucleophilic substitution, Parkinson's disease, Dopamine transporter