Exploration of alcohol-enhanced Cu-mediated radiofluorination towards practical labeling

187 Objectives: Significant progress has been reported recently in nucleophilic radiofluorination of aromatic compounds. Among these methods, alcohol-enhanced Cu-mediated nucleophilic substitution of aryl boron reagents appears to be a very promising approach due to the high radiochemical conversion (RCC) and the broad scope of available boron reagents. In the reported method, large amount of reactants (boron precursor (60 µmol) and Cu(OTf)2(Py)4 (26.6 µmol) in DMA (800 µL) and n-BuOH (400 µL)) were used to achieve high RCC. This protocol, however, is not practical for preparation of radiopharmaceuticals due to the cost of precursor, the challenge of manipulating the reaction mixture in automated synthesis modules, and the difficulty in purifying the desired product from starting reagents and the major protonated by-product. Our objectives were to explore the limiting factors in the method in order to optimize conditions for more practical labeling. Methods: Alcohol-enhanced Cu-mediated radiofluorination was carried out with 4-formylphenylbonic acid as the model compound under the reported condition with some modifications. Reactive [18F]fluoride ion was generated from [18F]tosyl fluoride (TsF) with known amounts of pre-dried K2CO3/K222, and the labeling was carried out in DMA/n-BuOH (9:1), which allows direct HPLC injection after dilution. Variation of reaction concentration and the amount of K2CO3/K222 and Cu(OTf)2(Py)4 was tested. Some carrier-added reactions (0.17 µmoL KF) were carried out to simulate radiofluorination in large scale. Other model compounds with different substituents were also tested. The reaction progress was analyzed by radio-TLC and radio-HPLC to determine the radioactive products, RCC and the formation of by-products. Results: Results from this preliminary study indicate that a linear correlation of RCC (or reaction rate) and concentration of reactants occurs at RCC 1 (2 for KHCO3/K222), the RCC drops sharply; at the same time, a color change in the reaction mixture and the formation of solids were observed. This indicates decomposition of Cu(OTf)2(Py)4 and suggests that the level of copper catalyst is critical for the reaction. The carrier-added reaction afforded similar RCC to the carrier-free reaction. Other model compounds also gave rise to similar RCC. No labeling was observed when water was present in the reaction. Conclusions: Our studies suggest that minimizing the reaction volume, maintaining the level of Cu(OTf)2(Py)4 and reducing the amount of base (i.e. K2CO3/K222) are critical to achieving high RCC under practical conditions for the preparation of 18F labeled radiopharmaceuticals. Radiolabeling of biologically relevant compounds using this strategy is under investigation. Research Support:NIH: CA25836 and WUSTL MIR Pilot fund