Rational Design, Pharmacomodulation, and Synthesis of Dual 5‑Hydroxytryptamine 7 (5-HT₇)/5-Hydroxytryptamine 2A (5-HT_2A) Receptor Antagonists and Evaluation by [¹⁸F]-PET Imaging in a Primate Brain

We report the synthesis of 46 tertiary amine-bearing <i>N</i>-alkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones, imidazo­[4,5-<i>c</i>]­pyridin-2­(3<i>H</i>)-ones, benzo­[<i>d</i>]­oxazol-2­(3<i>H</i>)-ones, oxazolo­[4,5-<i>b</i>]­pyridin-2­(3<i>H</i>)-ones and <i>N</i>,<i>N</i>′-dialkylated benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-ones. These compounds were evaluated against 5-HT₇R, 5-HT_2AR, 5-HT_1AR, and 5-HT₆R as potent dual 5-HT₇/5-HT_2A serotonin receptors ligands. A thorough study of the structure–activity relationship of the aromatic rings and their substituents, the alkyl chain length and the tertiary amine was conducted. 1-(4-(4-(4-Fluorobenzoyl)­piperidin-1-yl)­butyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>79</b>) and 1-(6-(4-(4-fluorobenzoyl)­piperidin-1-yl)­hexyl)-1<i>H</i>-benzo­[<i>d</i>]­imidazol-2­(3<i>H</i>)-one (<b>81</b>) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, <i>K</i>_B = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, <i>K</i>_B = 0.6 and 16 nM, respectively) signaling pathways of 5-HT₇R and 5-HT_2AR. Both antagonists crossed the blood–brain barrier as evaluated with [¹⁸F] radiolabeled compounds <b>[</b>^<b>18</b><b>F]­79</b> and <b>[</b>^<b>18</b><b>F]­81</b> in a primate’s central nervous system using positron emission tomography. Both radioligands showed standard uptake values ranging from 0.8 to 1.1, a good plasmatic stability, and a distribution consistent with 5-HT₇R and 5-HT_2AR in the CNS