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.
Highlights
Labeling with 18F is challenging due to the time constraints imposed by the short half-life (110 min), the need to manipulate minute amounts of [18F]fluoride, and the need for remote automated synthesis of tracers for clinical use. [18F]Fluoride can readily be produced with high specific activity (SA), and is by far the most common source of 18F for tracer synthesis
18F-labeling of aliphatic groups is sensitive to the presence of hydrogen bond donors, as well as neighbouring group effects, and as a result tracer synthesis often requires the use of prosthetic labeling reagents
Encouraged by the superb efficiency of the cycloaddition reaction in the presence of the bathophenanthrolinedisulfonic acid disodium salt hydrate (BPDS)-copper(I) catalytic system, we explored the possibility of preparing the triazoles [18F]6-[18F]9 in an one-pot reaction without distillation of the intermediate [18F]Fluoroethyl azide (FEA)
Summary
Labeling with 18F is challenging due to the time constraints imposed by the short half-life (110 min), the need to manipulate minute amounts of [18F]fluoride, and the need for remote automated synthesis of tracers for clinical use. [18F]Fluoride can readily be produced with high specific activity (SA), and is by far the most common source of 18F for tracer synthesis. Labeling with 18F is challenging due to the time constraints imposed by the short half-life (110 min), the need to manipulate minute amounts of [18F]fluoride, and the need for remote automated synthesis of tracers for clinical use. 18F-labeling of aliphatic groups is sensitive to the presence of hydrogen bond donors, as well as neighbouring group effects, and as a result tracer synthesis often requires the use of prosthetic labeling reagents. The copper(I)-catalyzed cycloaddition reaction of azides and alkynes to give 1,2,3-triazoles has recently emerged as a highly versatile method for conjugation of 18F-labeled „click‟ reagents to small molecules and peptides [1,2,3,4]. Despite the broad substrate scope, the efficiency of the reaction is dependent on the nature of the „click‟ partners, and conjugation to substrates with low reactivity or labile functional groups can be challenging [5]. Purification of the intermediate labeling reagent is often required prior to the cycloaddition reaction in order to limit the formation of side products
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