Syntheses, biological evaluation, and molecular modeling of ¹⁸F-labeled 4-anilidopiperidines as μ-opioid receptor imaging agents

The synthesis, evaluation, and molecular modeling of a series of ¹⁸F-labeled 4-anilidopiperidines with high affinities for the μ-opioid receptor (μ-OR) are reported. On the basis of the high brain uptake and selective retention in brain regions that contain a high concentration of the μ-OR, combined with a good metabolic stability, [ ¹⁸F]fluoro-pentyl carfentanil ([¹⁸F]4) and 2-(±)[¹⁸F]-fluoropropyl-sufentanil ([¹⁸F]6) were selected as the lead compounds for further evaluation. The binding affinity to the human μ-OR was 0.74 and 0.13 nM for [¹⁸F]4 and [ ¹⁸F]6, respectively. In vitro autoradiography of [¹⁸F] 4 and [¹⁸F] 6 on rat brain sections produced patterns in accordance with the known distribution of μ-OR expression. Structure-activity relationships of the fluorinated compounds are discussed with respect to the interaction with an activated-state model of the μ-OR. Taken together, the in vivo and in vitro data indicate that [¹⁸F] 4 and [¹⁸F] 6 hold promise for studying the μ-opioid receptor in humans by means of positron emission tomography.