Transition-metal-free reductive coupling of an 18F-labeled nitro-arene with boronic acids as a potential access to 18F-labeled fenamates

Objectives A recently developed synthetic route for the transition metal-free reductive coupling of aryl boronic acids with nitro1 or nitroso2 substituted arenes gives access to a variety of diaryl amines like fenamates.3 Radiotracers targeting COX-2 have been developed and tested as PET tracer but no clinically approved radiotracer emerged up to now. Aim of this project is to evaluate this novel synthetic route as a general access to 18F-labeled N,N-diaryl amines which are principally not activated for 18F-labeling by nucleophilic aromatic substitution, and by that access to fenamates like flufenamic acid as COX-targeting radiotracers in a wider sense. In this report, we present first results with focus on radiolabeling and reactivity of an asymmetric 18F-labeled nitro-arene. Methods The asymmetric sydnone-substituted nitroarene was radiolabeled under optimized conditions with fluorine-18 using K222/K2CO3 in DMF at 90°C and was purified by a C18-based solid phase extraction (SPE). Elution from the dried C18 SPE-cartridge with ortho-dichlorobenzene over a SEP-Pak Dry cartridge provided the intermediate [18F]A for further testing and optimization of the reductive coupling step. Subsequent radiochemical conversion of [18F]A with different boronic acids was monitored via radio-UHPLC. 3-Cyanophenyl boronic acid was used to optimize the coupling reaction with [18F]A with respect to the parameters base/reducing agent, temperature, reaction time. Furthermore, [18F]A was subjected to the reaction with other ortho-, meta-, and para-substituted boronic acids to get a first impression about the scope of this reaction. Results [18F]A was isolated after radiolabeling and purification by SPE in 16-54% isolated RCY (n=4). Optimizations using aliquots of 50 µL allowed for optimization of several reaction conditions with one batch of [18F]A. Triphenylphosphine but not triethylphosphite was found to mediate the reductive coupling of 3-cyanophenylboronic acid at reaction temperatures