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.
Emond
Patrick
P
INSERM U316, Laboratoire de Biophysique Médicale et Pharmaceutique, 31 Avenue Monge, 37200 Tours, France. emond@univ-tours.fr
Vercouillie
Johnny
J
Innis
Robert
R
Chalon
Sylvie
S
Mavel
Sylvie
S
Frangin
Yves
Y
Halldin
Christer
C
Besnard
Jean-Claude
JC
Guilloteau
Denis
D
D001665:Binding Sites / Q000502:physiology; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003287:Contrast Media / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins; D013379:Substrate Specificity; D013440:Sulfides / Q000138:chemical synthesis* / Q000494:pharmacology; D014055:Tomography, Emission-Computed
D002352:Carrier Proteins; D003287:Contrast Media; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D013440:Sulfides; D012701:Serotonin