7-[¹⁸F]Fluoro-8-azaisatoic Anhydrides: Versatile Prosthetic Groups for the Preparation of PET Tracers

Abstract

18 F-Fluorination of sensitive molecules is often challenging, but can be accomplished under suitably mild conditions using radiofluorinated prosthetic groups (PGs). Herein, 1-alkylamino-7-[ 18 F]fluoro-8-azaisatoic anhydrides ([ 18 F]AFAs) are introduced as versatile 18 F-labeled building blocks that can be used as amine-reactive or "click chemistry" PGs. [ 18 F]AFAs were efficiently prepared within 15 min by "on cartridge" radiolabeling of readily accessible trimethylammonium precursors. Conjugation with a range of amines afforded the corresponding 2-alkylamino-6-[ 18 F]fluoronicotinamides in radiochemical conversions (RCCs) of 15−98%. In addition, radiolabeling of alkyne-or azide-functionalized precursors with azidopropyl-or propargyl-substituted [ 18 F]AFAs using Cu-catalyzed click cycloaddition afforded the corresponding conjugates in RCCs of 44−88%. The practical utility of the PGs was confirmed by the preparation of three 18 F-labeled PSMA ligands in radiochemical yields of 28−42%. Biological evaluation in rats demonstrated excellent in vivo stability of all three conjugates. In addition, one conjugate ([ 18 F]JK-PSMA-15) showed favorable imaging properties for high-contrast visualization of small PSMA-positive lesions.