¹⁸F-Labeling Using Click Cycloadditions

Abstract

Due to expanding applications of positron emission tomography (PET) there is a demand for developing new techniques to introduce fluorine-18 (t 1/2 = 109.8 min). Considering that most novel PET tracers are sensitive biomolecules and that direct introduction of fluorine-18 often needs harsh conditions, the insertion of 18F in those molecules poses an exceeding challenge. Two major challenges during 18F-labeling are a regioselective introduction and a fast and high yielding way under mild conditions. Furthermore, attention has to be paid to functionalities, which are usually present in complex structures of the target molecule. The Cu-catalyzed azide-alkyne cycloaddition (CuAAC) and several copper-free click reactions represent such methods for radiolabeling of sensitive molecules under the above-mentioned criteria. This minireview will provide a quick overview about the development of novel 18F-labeled prosthetic groups for click cycloadditions and will summarize recent trends in copper-catalyzed and copper-free click 18F-cycloadditions.

A Practical Guide on the Synthesis of Metal Chelates for Molecular Imaging and Therapy by Means of Click Chemistry

“…In addition, novel practical methods for synthesis of azide-o ra lkyne-decorated functional molecules are continuously being developed, [6] for example, the direct conversion of the N-terminus of ar esin-bound peptidei nto an azide, which provides facile access to clickablep eptides withoutt he necessity of coupling extra buildingb locks, [11] or the continuous synthesis of azides from primary amines by diazo transfer in ac opper-tubeflow reactor. [15] These approaches generally involve inital synthesis and purificationo f ar adiofluorinated prosthetic group containing an alkyne or azide moiety,w hich is subsequently 'clicked' to the targeting vector.T he situation is slightly different for metal radionuclides which cannot be directlyi ncorporated into organic frameworks by covalent bonding. [13,14] For example, al arge variety of click-chemistry-based methods for the introduction of 18 Fl abels has been reported in the past few years,i mproving the synthetic accessibility of radiofluorinated tracers for positron emission tomography (PET).…”

Ortho‐Stabilized 18F‐Azido Click Agents and their Application in PET Imaging with Single‐Stranded DNA Aptamers

“…[2] Huisgen reactions (1,3-dipolar cycloaddition between azide and alkyne in a chemoselective and regiospecific manner) are the most routinely-used bioconjugation strategy. [3] The resulting 1,2,3-triazole linker is stable in vivo [4] , and considered to be an isosteric surrogate for peptide bonds. [5] Compared to many applications of azides in non-radioactive bioconjugation, only a small number of 18 F-labeled azides have been developed for PET radiochemistry, [3] among which only limited examples are attractive for routine production for PET imaging, and is likely attributed to lengthy multi-step syntheses with short half-life 18 F and/or requirement of special handling due to strong ionization energy.…”

“…[3] The resulting 1,2,3-triazole linker is stable in vivo [4] , and considered to be an isosteric surrogate for peptide bonds. [5] Compared to many applications of azides in non-radioactive bioconjugation, only a small number of 18 F-labeled azides have been developed for PET radiochemistry, [3] among which only limited examples are attractive for routine production for PET imaging, and is likely attributed to lengthy multi-step syntheses with short half-life 18 F and/or requirement of special handling due to strong ionization energy. For instance, [ 18 F]fluoroethyl azide was the first aliphatic 18 F-azide, prepared in high yield (55%, decay corrected) via a nucleophilic displacement reaction with [ 18 F]fluoride.…”

Click Chemistry and Radiochemistry: The First 10 Years

“…Much, although not all, of this work has focused on 18 F. 35–38 Indeed, a variety of radiosynthetic methods have been employed to create azide- and alkyne-bearing 18 F-labeled prosthetic groups (Figure 2A). 37,39,40 These tools and the CuAAC reaction have been harnessed with great success in the radiolabeling of a wide variety of vectors, including phosphonium ions, 41 peptides, 42–50 oligonucleotides, 39,47 and proteins. 27,47 This application of the CuAAC reaction is not without its flaws, however.…”