• nucleophilic fluorination;
  • fluorine-18;
  • fluoro-l-proline;
  • pulmonary fibrosis;
  • radiolabeling;
  • PET

Fluorine-18 labeled (2S,4S)-4-fluoro-l-proline (cis-[18F]4-FPro) has been reported to be a potential positron emission tomography tracer to study abnormal collagen synthesis occurring in pulmonary fibrosis, osteosarcomas, mammary and colon carcinomas. In this paper, we report the stereospecific radiofluorination of (2S,4R)-N-tert-butoxycarbonyl-4-(p-toluenesulfonyloxy) proline methyl ester (at 110°C) to produce diastereomerically pure cis-[18F]4-FPro in 38% radiochemical yield at the end of a 90-min synthesis. Investigation of the effect of temperature on the stereospecificity of nucleophilic fluorination showed that diasteriomerically pure cis-[18F]4-FPro or trans-[18F]4-FPro was produced at lower temperatures (85°C–110°C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130°C–145°C), fluorination of (2S,4R) precursor produced a mixture of cis-[18F]4-FPro and trans-[18F]4-FPro diastereomers with cis-[18F]4-FPro as the predominant isomer. Hydrolysis of the purified fluorinated intermediate was carried out either in one step, using 2 m triflic acid at 145°C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110°C for 10 min followed by stirring at room temperature in 1 N NaOH for 5 min. The aqueous hydrolysis mixture was loaded onto an anion exchange column (acetate form for one-step hydrolysis) or an ion retardation column (two-step hydrolysis) followed by a C18 Sep-Pak® (Waters Corporation, Milford, MA, USA). Pure cis-[18F]4-FPro was then eluted with sterile water. We also report that epimerization of cis-[18F]4-FPro occurs during the two-step hydrolysis (H+ followed by OH) of the intermediate, resulting in 5 ± 3% trans-[18F]4-FPro, whereas the one-step acid hydrolysis yielded pure cis-[18F]4-FPro in the final product. Copyright © 2011 John Wiley & Sons, Ltd.