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Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide
Department of Chemistry and Institute of Nuclear Medicine, University College London, 235 Euston Road (T-5), London, NW1 2BU, UK
Department of Chemistry, University of Oslo, PO Box 1033, Blindern N-0315, Oslo, Norway
Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, 33 Queen Square, London, WC1N 3BG, UK
* Author to whom correspondence should be addressed.
Received: 8 April 2013; in revised form: 16 April 2013 / Accepted: 3 May 2013 / Published: 10 May 2013
Abstract: 2-[18F]Fluoroethyl azide ([18F]FEA) can readily be obtained by nucleophilic substitution of 2-azidoethyl-4-toluenesulfonate with [18F]fluoride (half-life 110 min), and has become widely used as a reagent for ‘click’ labeling of PET tracers. However, distillation of [18F]FEA is typically required, which is time-consuming and unpractical for routine applications. In addition, copper(I)-catalyzed cycloaddition of [18F]FEA with non-activated alkynes, and with substrates containing labile functional groups, can be challenging. Herein, we report a highly efficient and practical ligand-accelerated one-pot/two-step method for ‘click’ labeling of small molecule tracers with [18F]FEA. The method exploits the ability of the copper(I) ligand bathophenanthrolinedisulfonate to accelerate the rate of the cycloaddition reaction. As a result, alkynes can be added directly to the crude reaction mixture containing [18F]FEA, and as cyclisation occurs almost immediately at room temperature, the reaction is tolerant to labile functional groups. The method was demonstrated by reacting [18F]FEA with a series of alkyne-functionalized 6-halopurines to give the corresponding triazoles in 55–76% analytical radiochemical yield.
Keywords: fluorine-18; click chemistry; BPDS; 2-[18F]fluoroethyl azide; 6-halopurine; automated synthesis; 1,2,3-triazole; PET; radiotracer
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Galante, E.; Schoultz, B.W.; Koepp, M.; Årstad, E. Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide. Molecules 2013, 18, 5335-5347.
Galante E, Schoultz BW, Koepp M, Årstad E. Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide. Molecules. 2013; 18(5):5335-5347.
Galante, Eva; Schoultz, Bent W.; Koepp, Matthias; Årstad, Erik. 2013. "Chelator-Accelerated One-Pot ‘Click’ Labeling of Small Molecule Tracers with 2-[18F]Fluoroethyl Azide." Molecules 18, no. 5: 5335-5347.