Copper-free sydnone-alkyne cycloaddition for the fluorine-18-radiolabeling of biologics

Complete text of publication follows: Objectives Among bio-orthogonal reactions, strain-promoted azide-alkyne cycloaddition (SPAAC) reaction is one of the most popular copper-free click tool for in vitro and in vivo applications.1 These selective, rapid and high yielding click reactions are widely used for the radiolabeling of biologics and subsequent applications in Positron Emission Tomography (PET).2 Electron-deficient sydnones undergo copper-free cycloadditions with cyclooctynes in very short reaction times, which is a decisive criterion when fluorine-18 is considered.3 We report the synthesis and fluorine-18-radiolabeling of a cyclooctyne derivative and its use in sydnone-alkyne copper-free click reaction. Methods Chemistry: The functionalization of BCN and DBCO, two popular cyclooctynes, was investigated. Reference compounds 3 and 12 and corresponding to syloxy precursors 5 and 11, respectively were prepared. Fluoro-cyclooctyne 3 was reacted with a chloro-sydnone model compound under copper-free click reaction conditions to afford final reference compound 6. Radiochemistry: Tosyl-oxy-precursor 5 in solution in DMSO was reacted with the activated K[¹⁸F]F-K222 complex of fluorine-18 for 5 min at 80 C. Radiolabeling of precursor 11 to prepare [¹⁸F]-12 is in progress. Results Starting from the commercially available BCN 1, compounds 3 and 5 were then obtained after only 2 and 3 steps in 34% and 18% overall yields, respectively. Copper-free click reaction of 3 with a phenyl-chloro-sydnone afforded compound 6 in 82% yields. Reference and precursor based on DBCO-NH2 were prepared in 4 and 3 steps in 15% and 30% overall yields, respectively. [¹⁸F]-3 was prepared in 24% RCY, observed by radio-HPLC. Conclusions Based on BCN and DBCO-NH2 cyclooctynes, two couples of precursors and references were prepared to explore the applications of the sydnone-alkyne copper-free click reaction to radiolabel biologics