13.1.2 The Use of Conventional Click Chemistry Reactions
in Radiochemistry
The refined version of the original Huisgen 1,3-dipolar cycloaddition reaction was
quickly recognised by radiochemists as a valuable tool for the production of
positron emission tomography (PET) and single-photon emission computed
tomography (SPECT) imaging agents [7, 8]. The radiosynthesis and isolation of
these imaging agents is often rendered challenging by the short radioactive
half-lives of many important radioisotopes (such as carbon-11 [t 1/2 = 20.3 min] and
fluorine-18 [t 1/2 = 109.8 min]) and therefore the rapid, facile, and clean nature of
click chemistry reactions make them well-suited to these applications.
The attractiveness of the Huisgen 1,3-dipolar cycloaddition reaction in radiochemistry is also attributable to the ease with which azide and alkyne substituents
can be incorporated into a range of chemical scaffolds. These functional groups also
exhibit kinetic stability and inertness towards a range of other chemical species and
reaction conditions. As such, azide and alkyne groups can frequently be incorporated early on during a multi-step synthesis often without risk of degradation or
transformation, thereby offering flexibility in terms of chemical synthetic strategies.
There are several examples in which the Huisgen 1,3-dipolar cycloaddition
reaction has been utilised in the preparation of radiolabeled small molecules [9, 10],
peptides [11–15], proteins [16, 17], and nanomaterials [18, 19]. In 2009, Devaraj
et al. reported the synthesis and preclinical in vivo evaluation of an [
18 F]-labeled
trimodal nanoparticle ([
18 F]-CLIO) constructed around a core of superparamagnetic
iron oxide that was cross-linked with dextran molecules [18]. During the preparation of these nanoparticles, surface modifications were made with both the
near-infrared fluorochrome VT680 and azide groups, the latter of which facilitated a
copper-catalysed click chemistry reaction with the radiofluorinated alkyne compound [
18 F]-PEG 3 . This nanoparticle radiolabelling strategy was shown to be
moderately efficient as an average decay-corrected radiochemical yield of 57% was
obtained under relatively mild reaction conditions (40 °C) and although DMSO was
used as a partial solvent in this reaction, the resulting [
18 F]-CLIO nanoparticles
were isolated very simply via microcentrifuge filtration and resuspension. The
average specific activity was 11 mCi mg
−1 of nanoparticles. While no diseasetargeting ligands were attached to the nanoparticles in this study, the remaining
azide groups present on the exterior represent an attractive opportunity for further
functionalisation.
In another example, copper-catalysed click chemistry has also been applied in
the preparation of [
18 F]-labeled nanoparticles of zinc oxide (ZnO) with the objective of understanding the effects of exposure to nanoparticles of this type upon the
body [19]. In this case, ZnO nanoparticles of two different sizes (20 or 100 nm)
were coated with alkyne residues and were then subjected to reaction with the
radiofluorinated compound, [
18 F]-ethoxy azide. In a similar fashion to the previous
example, the radiolabeled nanoparticles were purified via filtration and obtained in
13 Preservation of Ligand Functionality by Click Chemistry
253
in Radiochemistry
The refined version of the original Huisgen 1,3-dipolar cycloaddition reaction was
quickly recognised by radiochemists as a valuable tool for the production of
positron emission tomography (PET) and single-photon emission computed
tomography (SPECT) imaging agents [7, 8]. The radiosynthesis and isolation of
these imaging agents is often rendered challenging by the short radioactive
half-lives of many important radioisotopes (such as carbon-11 [t 1/2 = 20.3 min] and
fluorine-18 [t 1/2 = 109.8 min]) and therefore the rapid, facile, and clean nature of
click chemistry reactions make them well-suited to these applications.
The attractiveness of the Huisgen 1,3-dipolar cycloaddition reaction in radiochemistry is also attributable to the ease with which azide and alkyne substituents
can be incorporated into a range of chemical scaffolds. These functional groups also
exhibit kinetic stability and inertness towards a range of other chemical species and
reaction conditions. As such, azide and alkyne groups can frequently be incorporated early on during a multi-step synthesis often without risk of degradation or
transformation, thereby offering flexibility in terms of chemical synthetic strategies.
There are several examples in which the Huisgen 1,3-dipolar cycloaddition
reaction has been utilised in the preparation of radiolabeled small molecules [9, 10],
peptides [11–15], proteins [16, 17], and nanomaterials [18, 19]. In 2009, Devaraj
et al. reported the synthesis and preclinical in vivo evaluation of an [
18 F]-labeled
trimodal nanoparticle ([
18 F]-CLIO) constructed around a core of superparamagnetic
iron oxide that was cross-linked with dextran molecules [18]. During the preparation of these nanoparticles, surface modifications were made with both the
near-infrared fluorochrome VT680 and azide groups, the latter of which facilitated a
copper-catalysed click chemistry reaction with the radiofluorinated alkyne compound [
18 F]-PEG 3 . This nanoparticle radiolabelling strategy was shown to be
moderately efficient as an average decay-corrected radiochemical yield of 57% was
obtained under relatively mild reaction conditions (40 °C) and although DMSO was
used as a partial solvent in this reaction, the resulting [
18 F]-CLIO nanoparticles
were isolated very simply via microcentrifuge filtration and resuspension. The
average specific activity was 11 mCi mg
−1 of nanoparticles. While no diseasetargeting ligands were attached to the nanoparticles in this study, the remaining
azide groups present on the exterior represent an attractive opportunity for further
functionalisation.
In another example, copper-catalysed click chemistry has also been applied in
the preparation of [
18 F]-labeled nanoparticles of zinc oxide (ZnO) with the objective of understanding the effects of exposure to nanoparticles of this type upon the
body [19]. In this case, ZnO nanoparticles of two different sizes (20 or 100 nm)
were coated with alkyne residues and were then subjected to reaction with the
radiofluorinated compound, [
18 F]-ethoxy azide. In a similar fashion to the previous
example, the radiolabeled nanoparticles were purified via filtration and obtained in
13 Preservation of Ligand Functionality by Click Chemistry
253