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

F-Labeled building blocks from the type of [F]fluorophenylazocarboxylic--butyl esters offer a rapid, mild, and reliable method for the F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds and with single-digit and sub-nanomolar affinity for the D3 receptor and compound 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-[F]fluorophenylazocarboxylic--butyl ester was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives (). With the substituted [F]fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by F-fluoroarylation, namely the methoxy azocarboxamide as the D3 receptor radioligand and as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [F]fluorophenylazocarboxylic--butyl esters, the method of F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography .