Copper-free click chemistry with the short-lived positron emitter fluorine-18

The copper-free strain-promoted click chemistry between F-18-labeled aza-dibenzocyclooctyne [F-18]FB-DBCO and various azides is described. [F-18] FB-DBCO was prepared in 85% isolated radiochemical yield (decay-corrected) through acylation of amino aza-dibenzocyclooctyne 1 with N-succinimidyl 4-[F-18] fluorobenzoate ([F-18] SFB). [F-18] FB-DBCO showed promising radiopharmacological profil with fast blood clearance as assessed with dynamic small animal PET studies. Metabolic stability of [F-18] FB-DBCO was 60% of intact compound after 60 min post injection in normal Balb/C mice and blood clearance half-life was determined to be 53 s based on the time-activity-curve (TAC). Copper-free click chemistry was performed with various azides at low concentrations (1-2 mu M) which differed in their structural complexity in different solvents (methanol, water, phosphate buffer and in bovine serum albumin (BSA) solution). Reaction proceeded best in methanol (> 95% yield after 15 min at room temperature), whereas reaction in BSA required longer reaction times of 60 min and 40 degrees C upon completion.