[(18)F]Fluorophenylazocarboxylates: Design and Synthesis of Potential Radioligands for Dopamine D3 and μ-Opioid Receptor

[Image: see text] (18)F-Labeled building blocks from the type of [(18)F]fluorophenylazocarboxylic-tert-butyl esters offer a rapid, mild, and reliable method for the (18)F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds 3d and 3e with single-digit and sub-nanomolar affinity for the D3 receptor and compound 4c with only micromolar affinity for the μ-opioid receptor, but enhanced selectivity for the μ-subtype in comparison to the lead compound AH-7921. A “minimalist procedure” without the use of a cryptand and base for the preparation of 4-[(18)F]fluorophenylazocarboxylic-tert-butyl ester [(18)F]2a was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives ([(18)F]2b–f). With the substituted [(18)F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by (18)F-fluoroarylation, namely the methoxy azocarboxamide [(18)F]3d as the D3 receptor radioligand and [(18)F]4a as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [(18)F]fluorophenylazocarboxylic-tert-butyl esters, the method of (18)F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of (18)F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography .