Methods for labeling the trifluoroacetyl group with carbon-11 or fluorine-18 exemplified by the preparation of [^sup 18^F/^sup 11^C]2,2,2-trifluoro-1-phenylethanone

Objectives: The trifluoroacetyl group has been exploited in the design of inhibitors for many enzymes [1,2], notably cytosolic phospholipase A2s (cPLA2s) which have been implicated in inflammatory diseases [3]. The strong electron-withdrawing effect of the trifluoromethyl group renders the carbonyl moiety very electrophilic and increases its propensity to form stable hydrates (hemiketals or hemithioketals). Moreover, the trifluoromethyl group may serve as a carboxylic acid bioisostere. Methods for labeling the trifluoroacetyl group with a positron-emitter have not been described hitherto and therefore this group rarely features in PET radiotracers. We recently reported gas phase preparations of high molar activity [11C]fluoroform [4] and moderate molar activity [18F]fluoroform [5]. We are exploring new reactions of these radiolabeled fluoroforms to access new radiolabeled chemotypes. Here we describe methods for labeling the trifluoroacetyl group with carbon-11 or fluorine-18, as exemplified by the preparation of [18F/11C]2,2,2-trifluoro-1-phenylethanone Methods: [11C]/[18F]fluoroform was prepared by passing [11C]CH4/[18F]CH3F over heated (270/280 °C) CoF3, respectively, and trapped in DMF (0.6−0.8 mL) at −40 °C. The radiolabeled fluoroform (250−350 MBq) solution was added to a t-BuOK solution in DMF (0.3 M, 50 or 150 µL, 15 or 45 µmol). Methylbenzoate (7 mg, 50 µmol) in DMF (0.1 mL) was then added and allowed to react at room temperature for 10 min. BEMP, KHMDS and P1-t-Bu were also examined as bases for this reaction. Finally, hydrochloric acid (12 M, 0.1 mL) was added to the reaction mixture and heated at 60 °C for 5 min. The reaction was then quenched with MeCN-water (3:1 v/v, 1 mL), and the mixture analyzed with reversed phase HPLC. Three methylbenzoic acid esters bearing a p-substituent (Br, OMe or NO2) were also tested in this reaction. Products were identified by their retention times. Results: [11C]2,2,2-trifluoro-1-phenylethanone and[18F]2,2,2-trifluoro-1-phenylethanonewere obtained in 84 ± 5 (n = 3) and 79 ± 7% yield, respectively (n = 3). Among the bases examined, t-BuOK and KHMDS gave the best yields. No desired product was observed from the use of a sterically hindered base (BEMP or P1-t-Bu), nor from the p-nitro substituted substrate. Reduced amount of t-BuOK (15 µmol) slightly lowered the yields of [11C]2,2,2-trifluoro-1-phenylethanone (65 ± 16%, n = 3). A novel labeling synthon, [11C]1-(4-bromophenyl)-2,2,2-trifluoroethanone, was also prep