ACS Medicinal Chemistry Letters
Letter
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chemical conversions may be possible by heating at elevated
temperatures and/or microwave irradiation. The 18F-labeled
cyclooctyne [18F]-4 as well as the clicked model compound
[18F]-12 demonstrated excellent serum stability over 2 h. These
findings will allow key radiochemical and molecular imaging
studies such as direct fluorination, peptide labeling, cell labeling,
and PET imaging using in vitro and potentially in vivo copper-
free click chemistry. Future work utilizing 18F-labeled cyclo-
octyne 4 and other derivatives of 5, with a particular focus on
rapid introduction of the 18F into the cyclooctyne moiety
(rather than relying on [18F]SFB), will be reported in due
course.
ASSOCIATED CONTENT
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S
* Supporting Information
Analytical data and experimental protocols. This material is
AUTHOR INFORMATION
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Corresponding Author
(13) Poloukhtine, A. A.; Mbua, N. E.; Wolfert, M. A.; Boons, G.-J.;
Popik, V. V. Selective Labeling of Living Cells by a Photo-triggered
Click Reaction. J. Am. Chem. Soc. 2009, 131, 15769−15776.
(14) Jewett, J. C.; Sletten, E. M.; Bertozzi, C. R. Rapid Cu-free Click
Chemistry with Readily Synthesized Biarylazacyclooctynones. J. Am.
Chem. Soc. 2010, 132, 3688−3690.
(15) Sletten, E. M.; Nakamura, H.; Jewett, J. C.; Bertozzi, C. R.
Difluorobenzocyclooctyne: Synthesis, Reactivity, and Stabilization by
8-Cyclodextrin. J. Am. Chem. Soc. 2010, 132, 11799−11855.
(16) Kuzmin, A.; Poloukhtine, A.; Wolfert, M. A.; Popik, V. V.
Surface Functionalization Using Catalyst-free Azide-alkyne Cyclo-
addition. Bioconjugate Chem. 2010, 21, 2076−2085.
(17) Schultz, M. K.; Parameswarappa, S. G.; Pigge, F. C. Synthesis of
a DOTA-biotin Conjugate for Radionuclide Chelation via Cu-free
Click Chemistry. Org. Lett. 2010, 12, 2398−2341.
Author Contributions
The manuscript was written by all authors. All authors have
given approval to the final version of the manuscript. R.D.C.
and S.H.H. contributed equally to this work.
Funding
This work was supported in part by the U.S. Department of
Energy (DE-SC0002061).
ACKNOWLEDGMENTS
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We thank H. R. Davison and D. Satpati for assistance with mass
spectroscopy and HPLC analysis and L. Planutyte and D. L.
Kukis for 18F production at the Center for Molecular and
Genomic Imaging at the University of California, Davis.
(18) Martin, M. E.; Parameswarappa, S. G.; O’Dorisio, M. S.; Pigge,
F. C.; Schultz, M. K. A DOTA-peptide Conjugate by Copper-free
Click Chemistry. Bioorg. Med. Chem. Lett. 2010, 20, 4805−4807.
(19) Rossin, R.; Verkerk, P. R.; van den Bosch, S. M.; Vulders, R. C.
M.; Verel, I.; Lub, J.; Robillard, M. S. In Vivo Chemistry for
Pretargeted Tumor Imaging in Live Mice. Angew. Chem. 2010, 122,
3308−3311.
(20) Rossin, R.; Verkerk, P. R.; van den Bosch, S. M.; Vulders, R. C.
M.; Verel, I.; Lub, J.; Robillard, M. S. In Vivo Chemistry for
Pretargeted Tumor Imaging in Live Mice. Angew. Chem., Int. Ed. 2010,
49, 3375−3378.
(21) Keliher, E. J.; Reiner, T.; Turetsky, A.; Hilderbrand, S. A.;
Weissleder, R. High-Yielding, Two-Step 18F Labeling Strategy for 18F-
PARP1 Inhibitors. ChemMedChem 2011, 6, 424−427.
(22) Li, Z.; Cai, H.; Hassink, M.; Blackman, M. L.; Brown, R. C.;
Conti, P. S.; Fox, J. M. Tetrazinetrans-cyclooctene Ligation for the
Rapid Construction of 18F Labeled Probes. Chem. Commun. 2010, 46,
8043−8045.
(23) Ametamey, S. M.; Honer, M. J.; Schubiger, P. A. Molecular
Imaging with PET. Chem. Rev. 2008, 108, 1501−1516.
(24) Lee, S.; Xie, J.; Chen, X. Peptides and Peptide Hormones for
Molecular Imaging and Disease Diagnosis. Chem. Rev. 2010, 110,
3087−3111.
(25) Hausner, S. H.; Marik, J.; Gagnon, M. K.; Sutcliffe, J. L. In Vivo
Positron Emission Tomography (PET) Imaging with an αvβ6 Specific
Peptide Radiolabeled Using 18F-“click” Chemistry: Evaluation and
Comparison with the Corresponding 4-[18F]fluorobenzoyl- and 2-
[18F]fluoropropionyl Peptides. J. Med. Chem. 2008, 51, 5901−5904.
(26) McBride, W. J.; Sharkey, R. M.; Karacay, H.; D’Souza, C. A.;
Rossi, E. A.; Laverman, P.; Chang, C.-H.; Boerman, O. C.;
ABBREVIATIONS
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ADIBO, azadibenzocyclooctyne; β+, positron; d.c. RCY, decay-
corrected radiochemical yield; DIEA, N,N-diisopropylethyl-
amine; DMF, N,N-dimethylformamide; DMSO, dimethyl
sulfoxide; K222, 1,10-diaza-4,7,13,16,21,24-hexaoxabicyclo-
[8.8.8]hexacosane; FBA, 4-fluorobenzoic acid; HPLC, high-
performance liquid chromatography; PET, positron emission
tomography; PBS, phosphate-buffered saline; SFB, N-succini-
midyl 4-fluorobenzamide; SPE, solid-phase extraction; Su,
succinimidyl; TFA, trifluoroacetic acid; TSTU, O-(N-succini-
midyl)-1,1,3,3-tetramethyluronium tetrafluoroborate; T1/2, half-
life.
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