Synthesis and evaluation of 2-(2′-((dimethylamino)methyl)-4′-(2-fluoroethoxy-substituted)phenylthio)benzenamine derivatives as potential positron emission tomography imaging agents for serotonin transporters

Article abstract of DOI:10.1016/j.bioorg.2020.103654

A series of diphenylsulfide derivatives with various substitutions at the 4-position on phenyl ring A and different lengths of the 2-fluoroethoxy-substituted side-chain at the 4′-position on ring B were synthesized and evaluated as potential positron emission tomography (PET) imaging agents for serotonin transporters (SERT). These ligands exhibited high SERT binding affinities (K_i = 0.11–1.3 nM) and the 4-methyl-substituted (4-Me) compounds 7a and 8a displayed excellent selectivity for SERT versus norepinephrine transporters (NET) (392- and 700-fold, respectively). In the parallel artificial membrane permeability assay (PAMPA), these ligands demonstrated moderate to high brain penetration, and the 4-Me analogs showed higher BBB permeability than the corresponding 4-F analogs. The 2-fluoroethoxy-substituted ligands showed higher metabolic stability and lower lipophilicity than 4-F-ADAM. [¹⁸F]7a-c were readily prepared using an automatic synthesizer and exhibited significant uptake and slow washout in rat brains. At 120 min after iv injection, [¹⁸F]7a exhibited the highest uptake in the midbrain, whereas [¹⁸F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [¹⁸F]7a in the hypothalamus and striatum was significantly decreased. The potent and highly selective SERT binding and the selective and reversible accumulation in SERT-rich brain regions suggested that [¹⁸F]7a is a promising lead for the further development of novel [¹⁸F]-labeled PET imaging agents for SERT binding sites in the brain.