Copper‐Mediated Radiofluorination of Aryl Pinacolboronate Esters: A Straightforward Protocol by Using Pyridinium Sulfonates

Abstract

Radiofluorination of arylboronic acids pinacol esters (arylBPin) mediated by copper triflate pyridine complex is one of the more promising synthetic approaches for the direct introduction of nucleophilic [18F]fluoride into non‐activated arenes and heteroarenes. However, the application of this method to the production of positron emission tomography (PET) radiotracers in automated synthesizers remains a challenging task. The choice of phase‐transfer catalyst (PTC) and corresponding base used for the generation of reactive [18F]fluoride species has a profound impact on the efficiency of the 18F‐fluorination process. Herein we report the development of a simple procedure involving trapping of the aqueous [18F]fluoride on a weak anion‐exchange resin (WAX) and its release by elution with pyridinium sulfonate in dimethyl acetamide. Obtained reactive [18F]fluoride was used as‐is in a copper‐catalyzed fluorination reaction employing pyridinium salt as both PTC and base. High radiochemical conversion rates (RCCs) achieved for a series of simple arylBPin substrates and 4‐[18F]fluoro‐D,L‐phenylalanine demonstrate the efficiency of this novel 18F‐processing approach. Notably, the proposed method obviates conventional azeotropic drying steps, solvents evaporation and/or changeover and can be implemented on commercial automated synthesizers.

Fast and efficient copper-mediated 18F-fluorination of arylstannanes, aryl boronic acids, and aryl boronic esters without azeotropic drying

“…Conventionally used azeotropic distillation with MeCN is time consuming and here we have replaced it with SPE by using anion exchange cartridges. Lately, the use of SPE for the drying of [ 18 F]fluoride has also been a widely studied method in copper-mediated 18 F-radiofluorination, but typically these methods have still utilized additional evaporation steps (Zischler et al 2017) or use of additional, sometimes toxic reagents (Antuganov et al 2019; Zhang et al 2019). Herein, we have described a simple method, which includes the use of Cu(OTf) 2 or Cu(OTf) 2 (py) 4 for the elution of [ 18 F]fluoride, and is suitable for automation and clinical production of radiopharmaceuticals.…”

“…Consequently, the latest developments include the replacement of azeotropic drying of [ 18 F]fluoride by solid phase extraction (SPE). The SPE process has been improved by using alcohols in the [ 18 F]fluoride processing (Zischler et al 2017) or pyridinium sulfonates (Antuganov et al 2019) or dimethylaminopyridinium triflates (DMAP) as an elution agents (Zhang et al 2019). However, these new [ 18 F]fluoride elution methods typically involve separate evaporation steps after the elution or utilize relatively toxic chemicals, like DMAP, which might not be necessary for the radiolabelling reaction itself.…”

Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

“…Furthermore, the use of organic solutions of PTCs in the elution process allowed to simplify automation and shorten synthesis time by omitting azeotropic drying step. In combination with this back-flushing protocol, organic solutions of other PTCs such as tetrabutyl ammonium triflate (Bu 4 NOTf) [ 82 ] and pyridinium sulphonates [ 83 ] have been found to be effective for the preparation of reactive [ 18 F]fluoride species for use in subsequent Cu-mediated fluorinations.…”

Indolylboronic Acids: Preparation and Applications

“…Both published procedures rely on Cu-mediated radiofluorination with different fluoride sources. Krasikova [140] achieved a radiochemical conversion (rcc) of 84% within 20 min in DMA at 110 °C under phase-transfer catalysis conditions. The same catalytic system was used by Neumaier, although in that case [ 18 F]F - was eluted with Et 4 NHCO 3 in n butanol [141].…”