The continual refinement of these reactions using innovative chemistry is offering
highly versatile synthetic methods which are becoming faster, simpler, and higher
yielding. In many cases, these reactions have offered a convenient and efficient
means of obtaining radiolabeled derivatives of ligands without compromising the
ligands’ functional ability to bind to its target epitope. The application of click
chemistry methods for the production of a wide variety of radiolabeled nanomaterials is also showing much promise. Lastly, bioorthogonal IEDDA chemistry has
now become established as the basis of a novel pretargeting strategy for both
nuclear imaging and therapeutic applications. Pretargeting methods based on
nanoparticle primary agents have demonstrated some efficacy despite in most cases
relying on passive tumour targeting via the EPR effect. Given the high ligand
loading capacity offered by most nanoparticles, it will be of interest to expand this
approach to include targeting of specific disease biomarkers.
References
1. H.C. Kolb, M.G. Finn, K.B. Sharpless, Click chemistry: diverse chemical function from a few
good reactions. Angew. Chem. Int. Ed. Engl. 40(11), 2004–2021 (2001)
2. M. Meldal, C.W. Tornøe, Cu-catalyzed azide–alkyne cycloaddition. Chem. Rev. 108(8),
2952–3015 (2008)
3. R. Huisgen, 1,3-dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl. 2(10),
565–598 (1963)
4. R. Huisgen, Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew. Chem. Int. Ed.
Engl. 2(11), 633–645 (1963)
5. V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, A stepwise Huisgen cycloaddition
process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew.
Chem. Int. Ed. Engl. 41(14), 2596–2599 (2002)
6. C.W. Tornøe, C. Christensen, M. Meldal, Peptidotriazoles on solid phase: [1,2,3]-triazoles by
regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides.
J. Org. Chem. 67(9), 3057–3064 (2002)
7. K. Nwe, M.W. Brechbiel, Growing applications of “click chemistry” for bioconjugation in
contemporary biomedical research. Cancer Biother Radiopharm. 24(3), 289–302 (2009)
8. C. Wängler, R. Schirrmacher, P. Bartenstein, B. Wängler, Click-chemistry reactions in
radiopharmaceutical chemistry: fast & easy introduction of radiolabels into biomolecules for
in vivo imaging. Curr. Med. Chem. 17(11), 1092–1116 (2010)
9. T.L. Ross, M. Honer, P.Y.H. Lam, T.L. Mindt, V. Groehn, R. Schibli et al., Fluorine-18 click
radiosynthesis and preclinical evaluation of a new
18
F-labeled folic acid derivative. Bioconjug
Chem. 19(12), 2462–2470 (2008)
10. E. Galante, W.B. Schoultz, M. Koepp, E. Årstad, Chelator-accelerated one-pot ‘Click’
labeling of small molecule tracers with 2-[
18
F] fluoroethyl azide. Molecules 18(5) (2013)
11. J. Marik, J.L. Sutcliffe, Click for PET: rapid preparation of [
18
F] fluoropeptides using CuI
catalyzed 1,3-dipolar cycloaddition. Tetrahedron Lett. 47(37), 6681–6684 (2006)
12. S.H. Hausner, J. Marik, M.K.J. Gagnon, J.L. Sutcliffe, In vivo positron emission tomography
(PET) imaging with an avb6 specific peptide radiolabeled using
18
F-“click” chemistry:
evaluation and comparison with the corresponding 4-[
18
F] fluorobenzoyl- and 2-[
18
F]
fluoropropionyl-peptides. J. Med. Chem. 51(19), 5901–5904 (2008)
13 Preservation of Ligand Functionality by Click Chemistry
259
highly versatile synthetic methods which are becoming faster, simpler, and higher
yielding. In many cases, these reactions have offered a convenient and efficient
means of obtaining radiolabeled derivatives of ligands without compromising the
ligands’ functional ability to bind to its target epitope. The application of click
chemistry methods for the production of a wide variety of radiolabeled nanomaterials is also showing much promise. Lastly, bioorthogonal IEDDA chemistry has
now become established as the basis of a novel pretargeting strategy for both
nuclear imaging and therapeutic applications. Pretargeting methods based on
nanoparticle primary agents have demonstrated some efficacy despite in most cases
relying on passive tumour targeting via the EPR effect. Given the high ligand
loading capacity offered by most nanoparticles, it will be of interest to expand this
approach to include targeting of specific disease biomarkers.
References
1. H.C. Kolb, M.G. Finn, K.B. Sharpless, Click chemistry: diverse chemical function from a few
good reactions. Angew. Chem. Int. Ed. Engl. 40(11), 2004–2021 (2001)
2. M. Meldal, C.W. Tornøe, Cu-catalyzed azide–alkyne cycloaddition. Chem. Rev. 108(8),
2952–3015 (2008)
3. R. Huisgen, 1,3-dipolar cycloadditions. Past and future. Angew. Chem. Int. Ed. Engl. 2(10),
565–598 (1963)
4. R. Huisgen, Kinetics and mechanism of 1,3-dipolar cycloadditions. Angew. Chem. Int. Ed.
Engl. 2(11), 633–645 (1963)
5. V.V. Rostovtsev, L.G. Green, V.V. Fokin, K.B. Sharpless, A stepwise Huisgen cycloaddition
process: copper(I)-catalyzed regioselective “ligation” of azides and terminal alkynes. Angew.
Chem. Int. Ed. Engl. 41(14), 2596–2599 (2002)
6. C.W. Tornøe, C. Christensen, M. Meldal, Peptidotriazoles on solid phase: [1,2,3]-triazoles by
regiospecific copper(I)-catalyzed 1,3-dipolar cycloadditions of terminal alkynes to azides.
J. Org. Chem. 67(9), 3057–3064 (2002)
7. K. Nwe, M.W. Brechbiel, Growing applications of “click chemistry” for bioconjugation in
contemporary biomedical research. Cancer Biother Radiopharm. 24(3), 289–302 (2009)
8. C. Wängler, R. Schirrmacher, P. Bartenstein, B. Wängler, Click-chemistry reactions in
radiopharmaceutical chemistry: fast & easy introduction of radiolabels into biomolecules for
in vivo imaging. Curr. Med. Chem. 17(11), 1092–1116 (2010)
9. T.L. Ross, M. Honer, P.Y.H. Lam, T.L. Mindt, V. Groehn, R. Schibli et al., Fluorine-18 click
radiosynthesis and preclinical evaluation of a new
18
F-labeled folic acid derivative. Bioconjug
Chem. 19(12), 2462–2470 (2008)
10. E. Galante, W.B. Schoultz, M. Koepp, E. Årstad, Chelator-accelerated one-pot ‘Click’
labeling of small molecule tracers with 2-[
18
F] fluoroethyl azide. Molecules 18(5) (2013)
11. J. Marik, J.L. Sutcliffe, Click for PET: rapid preparation of [
18
F] fluoropeptides using CuI
catalyzed 1,3-dipolar cycloaddition. Tetrahedron Lett. 47(37), 6681–6684 (2006)
12. S.H. Hausner, J. Marik, M.K.J. Gagnon, J.L. Sutcliffe, In vivo positron emission tomography
(PET) imaging with an avb6 specific peptide radiolabeled using
18
F-“click” chemistry:
evaluation and comparison with the corresponding 4-[
18
F] fluorobenzoyl- and 2-[
18
F]
fluoropropionyl-peptides. J. Med. Chem. 51(19), 5901–5904 (2008)
13 Preservation of Ligand Functionality by Click Chemistry
259