Rational Design, Pharmacomodulation, and Synthesis of Dual 5‑Hydroxytryptamine 7 (5-HT7)/5-Hydroxytryptamine 2A (5-HT2A) Receptor Antagonists and Evaluation by [18F]-PET Imaging in a Primate Brain

We report the synthesis of 46 tertiary amine-bearing N-alkylated benzo­[d]­imidazol-2­(3H)-ones, imidazo­[4,5-b]­pyridin-2­(3H)-ones, imidazo­[4,5-c]­pyridin-2­(3H)-ones, benzo­[d]­oxazol-2­(3H)-ones, oxazolo­[4,5-b]­pyridin-2­(3H)-ones and N,N′-dialkylated benzo­[d]­imidazol-2­(3H)-ones. These compounds were evaluated against 5-HT7R, 5-HT2AR, 5-HT1AR, and 5-HT6R as potent dual 5-HT7/5-HT2A 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)-1H-benzo­[d]­imidazol-2­(3H)-one (79) and 1-(6-(4-(4-fluorobenzoyl)­piperidin-1-yl)­hexyl)-1H-benzo­[d]­imidazol-2­(3H)-one (81) were identified as full antagonist ligands on cyclic adenosine monophosphate (cAMP, KB = 4.9 and 5.9 nM, respectively) and inositol monophosphate (IP1, KB = 0.6 and 16 nM, respectively) signaling pathways of 5-HT7R and 5-HT2AR. Both antagonists crossed the blood–brain barrier as evaluated with [18F] radiolabeled compounds [18F]­79 and [18F]­81 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-HT2AR in the CNS.