Effect of Pyridine Addition on the Efficiency of Copper‐Mediated Radiofluorination of Aryl Pinacol Boronates

Abstract

The rise of the transition‐metal‐mediated and/or catalyzed radiofluorination reactions has led us to investigate possibilities for the improvement of the radiolabeling yields of pinacol esters of arylboronic acids (arylBPin) in the presence of Cu(OTf)2(py)4. Addition of small amounts pyridine to the reaction medium with DMF as a solvent and [18F]F−/K222Cs+complex as [18F]fluoride source was shown to have a significant positive effect on the radiofluorination yields. The effect was investigated in depth using 4‐biphenylboronic acid pinacol ester as a model compound, with up to 20 % increase in radiochemical conversion observed at optimized conditions. Maximum effect was observed at pyridine‐to‐catalyst ratio of 30:1. The findings were applied to a representative electron‐rich ring systems that are traditionally difficult or impossible to radiolabel with nucleophilic fluoride, leading to products such as 2‐[18F]fluoroanisole and protected 4‐L‐[18F]fluorophenylalanine. Given the ever‐present pressure to develop new methods for introduction of fluorine‐18 into various substrates to facilitate easy and robust production of clinically‐relevant radiotracers for PET imaging we believe our findings can be of significant practical interest for radiofluorination of ortho‐substituted substrates in particular.

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

“…The eluate was collected into a 5 mL Wheaton V‐vial pre‐filled with 1 (Figure ), copper catalyst and 0.1 mL of DMF. Radiofluorinations were carried out under previously established conditions (Table ). Unfortunately, the EE of [ 18 F]fluoride was relatively poor for all the investigated sulfonate salts dissolved in DMF.…”

“…Synthesis of 2‐ or 4‐[ 18 F]FPhA was often executed to demonstrate the feasibility of Cu‐mediated fluorinations approaches. [3b], , Using arylBPin precursor 9 (Figure ) and our labeling protocol, the RCC for 9a was over 90 %. Following acid hydrolysis with 12 m HCl (130 °C, 10 min) and HPLC purification in the ethanol‐based mobile phase, 4‐[ 18 F]FPhA was obtained in RCY of 35–38 % (non‐optimized, corrected for radioactive decay) within 90 min.…”

“…Previously we have shown that addition of small amounts of pyridine to the reaction medium resulted in a significant boost to the copper‐catalyzed 18 F‐fluorination efficiency for various [ 18 F]fluoroanisoles, including ortho ‐substituted ones . The recent publication of the Scott group on the customized [ 18 F]fluoride elution technique reports the enhancement of the 18 F‐fluorination efficiency of arylBPin substrates .…”

“…Based on our previous report, we hypothesized that pyridinium sulfonates may serve as viable alternative catalysts for use in transition metal catalyzed fluorination reactions. These salts can serve both as a source of pyridine to increase efficiency of the copper catalyst, and as a PTC. Elution of [ 18 F]fluoride with an aqueous solution of pyridinium p ‐toluenesulfonate was earlier examined by Scott' group .…”

A Practical Method for the Preparation of 18F-Labeled Aromatic Amino Acids from Nucleophilic [18F]Fluoride and Stannyl Precursors for Electrophilic Radiohalogenation

“…Particularly, methods for transition metal mediated radiofluorination pioneered by Ritter et al and Coenen et al have the potential to change the paradigm of radiochemistry [ 1 , 2 , 3 ]. Obviously, procedures for Cu-mediated 18 F-fluorination discovered by Scott et al and Gouverneur et al [ 4 , 5 , 6 , 7 ] and further developed by inventors and others [ 8 , 9 , 10 , 11 , 12 ], enabling the preparation of 18 F-labeled aromatics and heteroaromatics regardless of their electronic properties using nucleophilic 18 F − have gained special interest. This is primarily due to the fact that these approaches do not require strictly controlled conditions (e.g., complete exclusion of oxygen and/or moisture), poorly accessible or extremely sensitive radiolabeling precursors.…”