The ¹⁸F‐labelled alkylating agent 2,2,2‐trifluoroethyl triflate: Synthesis and specific activity

Abstract

A method for synthesizing the alkylating agent 2,2,2-trifluoroethyl triflate labelled with [ 18FIfluoride in the two position is presented. Ethyl [2-l~F]-mfluoroacetate was synthesized by the nucleophilic reaction of [ 18FIF-with ethyl bromodifluoroacetate in DMSO (4560%. 5 min, 80 OC) and subsequently converted to [2-18F]-2,2,2-trifluoroethanol using alane in THF (85-95%, 2 min, 40 OC). Reaction with triflic anhydride in 2,6-lutidine produced [2-18F]-2,2,2-trifluoroethyl triflate (70-80%, 1 min, 0 OC). In all three cases the product was removed from the reaction vessel by heating to distil under a stream of nitrogen. [2-18F]-2,2,2-Trifluoroethyl triflate was used to label 2-oxoquazepam by N-alkylation in a to1uene:DMF mixture (80-85%, 20 min, 120 OC). Although no-carrier-added [18F]F-was used, considerable unlabelled ethyl trifluoroacetate was produced in the first reaction. Varying the conditions for the fluoro-debromination reaction did not appreciably improve the relative ratio of labelled to unlabelled ester. The specific activity of the labelled 1.4-benzodiazepine-2-one obtained from 1850 MBq [18F]F-was found to be =37 MBq/pmol (1 mCi/pinol).

Radiosynthesis of the tumor hypoxia marker [18F]TFMISO via O-[18F]trifluoroethylation reveals a striking difference between trifluoroethyl tosylate and iodide in regiochemical reactivity toward oxygen nucleophiles

“…However, when high specific activity is required, this 18 F- 19 F exchange-based method is disadvantageous compared to a no-carrier-added approach such as the one we tried in Approach A (Scheme 1) if a) elimination of the leaving group does not overwhelm its substitution with 18 F and b) no isotopic dilution occurs. It may be noteworthy that in labeling of a trifluoroalkyl group in a complex molecule with 18 F, which often involves unusual chemistry as reported here, even a no-carrier-added approach does not necessarily result in a high specific activity radiotracer 20 .…”

“…In the past, 18 F-labeling of the trifluoroethyl moiety in oxaquazepam, a benzodiazepine receptor antagonist, has been achieved using 2,2,2-[ 18 F]trifluoroethyl triflate, which was prepared via a 3 step procedure 20 . The trifluoropropyl moiety of EF3, a hypoxia marker and a potential bimodal probe, has also been labeled with 18 F via a 5-step method using [ 18 F]-poly(hydrogen fluoride)pyridinium as the precursor 21 .…”

PET radioligands targeting the brain GABAA/benzodiazepine receptor complex

“…Finally, [N-[2-18 F]-2,2,2-trifluoroethyl]-2-oxoquazepam has been labeled using [2-18 F]-2,2,2-trifluoroethyl triflate as alkylating agent; however, the specific radioactivity was very low when this method was used because of severe isotopic dilution during the fluoro-debromination reaction in the [2-18 F]-2,2,2-trifluoroethyl triflate synthesis. 20 We were however not able to find any published PET data with 18 F-labeled 2-oxoquazepam.…”

“…[2′‐ 18 F]‐2‐Oxoquazepam has also been labeled by a multistep method starting from nucleophilic substitution of [ 18 F]F − into 2‐[ 18 F]fluorobenzaldehyde, which was coupled with an anilinodichloroborane to obtain 5‐chloro‐2′‐[ 18 F]fluoro‐2‐( N ‐(2,2,2‐trifluoroethyl)amino)benzhydrol, further oxidized to the benzophenone and reacted with bromoacetyl bromide to generate the bromoacetamide and finally ring closure to obtain the 1,4‐benzodiazepine‐2‐one (Scheme ). Finally, [ N ‐[2‐ 18 F]‐2,2,2‐trifluoroethyl]‐2‐oxoquazepam has been labeled using [2‐ 18 F]‐2,2,2‐trifluoroethyl triflate as alkylating agent; however, the specific radioactivity was very low when this method was used because of severe isotopic dilution during the fluoro‐debromination reaction in the [2‐ 18 F]‐2,2,2‐trifluoroethyl triflate synthesis . We were however not able to find any published PET data with 18 F‐labeled 2‐oxoquazepam.…”

Contrast Agents II

“…M.-C. Lasne [249]. Protection of the carboxylic functionality in an oxazoline ring appeared necessary to reach high specific activities [250].…”