Automated, Resin-Based Method to Enhance the Specific Activity of Fluorine-18 Clicked PET Radiotracers

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• 作者：Federica Pisaneschi ; Lindsay E. Kelderhouse ; Amanda Hardy ; Brian J. Engel ; Uday Mukhopadhyay ; Carlos Gonzalez-Lepera ; Joshua P. Gray ; Argentina Ornelas ; Terry T. Takahashi ; Richard W. Roberts ; Stephen V. Fiacco ; David Piwnica-Worms ; Steven W. Millward
• 刊名：Bioconjugate Chemistry
• 出版年：2017
• 出版时间：February 15, 2017
• 年：2017
• 卷：28
• 期：2
• 页码：583-589
• 全文大小：410K
• ISSN：1520-4812

文摘

Radiolabeling of substrates with 2-[¹⁸F]fluoroethylazide exploits the rapid kinetics, chemical selectivity, and mild conditions of the copper-catalyzed azide–alkyne cycloaddition reaction. While this methodology has proven to result in near-quantitative labeling of alkyne-tagged precursors, the relatively small size of the fluoroethylazide group makes separation of the ¹⁸F-labeled radiotracer and the unreacted precursor challenging, particularly with precursors >500 Da (e.g., peptides). We have developed an inexpensive azide-functionalized resin to rapidly remove unreacted alkyne precursor following the fluoroethylazide labeling reaction and integrated it into a fully automated radiosynthesis platform. We have carried out 2-[¹⁸F]fluoroethylazide labeling of four different alkynes ranging from <300 Da to >1700 Da and found that >98% of the unreacted alkyne was removed in less than 20 min at room temperature to afford the final radiotracers at >99% radiochemical purity with specific activities up to >200 GBq/μmol. We have applied this technique to label a novel cyclic peptide previously evolved to bind the Her2 receptor with high affinity, and demonstrated tumor-specific uptake and low nonspecific background by PET/CT. This resin-based methodology is automated, rapid, mild, and general allowing peptide-based fluorine-18 radiotracers to be obtained with clinically relevant specific activities without chromatographic separation and with only a minimal increase in total synthesis time.