Temperature effects on the stereospecificity of nucleophilic fluorination: formation of trans-[18F]4-fluoro-l-proline during the synthesis of cis-[18F]4-fluoro-l-proline

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 degrees 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 degrees C110 degrees C) during the fluorination of (2S,4R) or (2S,4S) precursors, respectively. However, at higher temperatures (130 degrees C145 degrees 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 degrees C for 10 min, or in two steps where the intermediate was heated in 1 m HCl at 110 degrees 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 (R) (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 (C) 2011 John Wiley & Sons, Ltd.