Substituted diphenyl sulfides as selective serotonin transporter ligands: synthesis and in vitro evaluation

A series of diphenyl sulfide derivatives substituted at the 1-, 2'-, and 4'-positions has been synthesized and evaluated for their in vitro affinities at the dopamine, serotonin (SERT), and norepinephrine transporters. The examination of K(i) values revealed that most of these derivatives have high affinity and selectivity for the SERT. Moreover, substitutions at these positions differently influence the SERT binding: (i) The nature of the substituent linked at the 1-position critically influences the SERT affinity. (ii) Functions containing heteroatom at the 2'-position afford compounds with high SERT affinity. (iii) The nature of the substituent at the 4'-position slightly influences the SERT affinity whereas steric effect markedly decreases the SERT affinity. From this series, the most SERT selective derivatives (such as 8b, 8c, and 8g) are now evaluated for their potential as positron emission tomography imaging agents when labeled with carbon-11.