Improvements to the radiosynthesis of [¹⁸F]nifene

Objectives [¹⁸F]Nifene is a radioligand developed to study α4β2 nicotinic acetylcholine receptors with rapid equilibration. Previous methods for the production of radiolabeled [¹⁸F]nifene presented challenges in completely separating intermediate N-boc-[¹⁸F]nifene from the precursor and prolonged radiosynthesis times. Changes to the semi-prep HPLC separation method and other steps in the radiosynthesis were examined with the goal of improving the ease and quality of [¹⁸F]nifene production.

Methods Variations to the HPLC conditions were examined in the context of separating N-boc-[¹⁸F]nifene from nifene precursor. The intermediate was then deprotected and examined on analytic HPLC for chemical purity. Different methods to ensure the fast removal of residual N-boc-[¹⁸F]nifene from the final [¹⁸F]nifene product were also examined.

Results The use of the organic solvent tetrahydrofuran (THF) to create a 3-solvent mobile phase improved peak resolution. A mobile phase of 55% 0.05 M NaOAc, 27% MeOH, and 18% THF at a flow rate of 8.0 ml min^-1 with a C-18 Prodigy (Phenomenex) 10 μm 250×10 mm column was found to qualitatively remove all residual precursor. End of synthesis chemical purities were found to exceed 95% with no detectable precursor in the analytic chromatogram. The removal of intermediate N-boc-[¹⁸F]nifene from [¹⁸F]nifene following deprotection was found to be quickly performed by adding 10% EtOH to the diluted product and passing the solution through a C-18 sep-pak. In total, these changes to the radiosynthesis of [¹⁸F]nifene produced 10-20% decay corrected radiochemical yield in quantities sufficient for a standard PET scan procedure. Total synthesis time was 1.5 hours, 1 hour shorter than previous methods. Specific activities were consistently in excess of 200 GBq µmol^-1, a 4-fold improvement.

Conclusions The changes to the [¹⁸F]nifene radiosynthesis discussed here reduced the synthesis time required and improved final product chemical purity and specific activity, improving the ease and quality of [¹⁸F]nifene production.

Research Support AA017706, CA14218