A rapid and highly enantioselective C-¹¹C bond formation of l-[¹¹C]phenylalanine via chiral phase-transfer catalysis

A rapid method for the synthesis of carbon-11 radiolabeled phenylalanine was developed using a chiral phase-transfer catalyst and a sub-nanomolar quantity of [¹¹C]benzyl iodide as a radio-precursor. Based on a reported synthesis of [¹¹C]benzyl iodide, a Schiff base precursor was evaluated for stereoselective [¹¹C]benzylation. Extensive and interactive screening of the precursor, catalyst, base, stirring and temperature was required to achieve high stereoinduction. The result is an efficient 5-step radiolabeling method to reliably synthesize l- or d-[¹¹C]phenylalanine with an excellent enantiomeric excess of >90% and almost quantitative radiochemical conversion of >95% (n > 5). Additionally, a phase-transfer catalyzed alkylation was utilized on the preparative scale using automated platform. The application resulted in high specific activity ranging from 85-135 GBq μmol⁻¹ of the enantiomerically pure [¹¹C]phenylalanine, showing that the process is robust and amenable to broad use in PET.