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

¹⁸F-Labeled building blocks from the type of [¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl esters offer a rapid, mild, and reliable method for the ¹⁸F-fluoroarylation of biomolecules. Two series of azocarboxamides were synthesized as potential radioligands for dopamine D3 and the μ-opioid receptor, revealing compounds <b>3d</b> and <b>3e</b> with single-digit and sub-nanomolar affinity for the D3 receptor and compound <b>4c</b> 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-[¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl ester <b>[</b>^<b>18</b><b>F]­2a</b> was established, together with the radiosynthesis of methyl-, methoxy-, and phenyl-substituted derivatives (<b>[</b>^<b>18</b><b>F]­2b–f</b>). With the substituted [¹⁸F]­fluorophenylazocarbylates in hand, two prototype azocarboxylates radioligands were synthesized by ¹⁸F-fluoroarylation, namely the methoxy azocarboxamide <b>[</b>^<b>18</b><b>F]­3d</b> as the D3 receptor radioligand and <b>[</b>^<b>18</b><b>F]­4a</b> as a prototype structure of the μ-opioid receptor radioligand. By introducing the new series of [¹⁸F]­fluorophenylazocarboxylic-<i>tert</i>-butyl esters, the method of ¹⁸F-fluoroarylation was significantly expanded, thereby demonstrating the versatility of ¹⁸F-labeled phenylazocarboxylates for the design of potential radiotracers for positron emission tomography