title: Fluorinated diaryl sulfides as serotonin transporter ligands: synthesis, structure-activity relationship study, and in vivo evaluation of fluorine-18-labeled compounds as PET imaging agents.
abstract: A series of new, fluorine-containing substituted diphenyl sulfides was synthesized to serve as candidate ligands for positron emission tomography (PET) imaging of the serotonin transporter (SERT) and to further probe the structure-activity relationship (SAR) of this class of compounds. Candidate compounds were assayed for their affinities to the monoamine transporters (SERT, norepinephrine transporter (NET), and dopamine transporter (DAT)) in competitive binding experiments in vitro using cloned human transporters. From these in vitro assays, four compounds (7c-f) were chosen for further evaluation. All four compounds have nanomolar affinity for SERT (K(i) 1.46 nM, 1.04 nM,1.83 nM, and 3.58 nM for 7c, 7d, 7e, and 7f, respectively). The F-18-labeled compounds, 16 and 18a-c, were prepared via a two-step radiosynthesis. Biodistribution studies in rats indicated that the F-18-labeled compounds localized in brain regions with high concentrations of SERT. Furthermore, competition experiments demonstrated that the binding of these radioligands in the rat brain was saturable, specific, and selective to SERT. Specific binding in the rat hypothalamus peaked at 5.6 for ligand 16 and 4.4 for 18b at 90 min after radioactivity administration. For ligand 18a, this same ratio was 8.4 at 120 min postinjection, while compound 18c displayed a lower specific binding ratio of 2.4. In summary, four F-18-labeled ligands were prepared and evaluated as candidate PET imaging agents for SERT. Among these four ligands, three appear to be promising radioligands suitable for the labeling of SERT in vivo, with 18a providing a higher specific binding in vivo than 16 or 18b.
authors.affiliation: Department of Psychiatry and Radiology, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Yiyun
authors.initials: Y
authors.lastname: Huang
authors.forename: Sung-A
authors.initials: SA
authors.lastname: Bae
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zhu
authors.forename: Ningning
authors.initials: N
authors.lastname: Guo
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Marc
authors.initials: M
authors.lastname: Laruelle
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D005462:Fluorine Radioisotopes; D006801:Humans; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
chemical_list: D001555:Benzene Derivatives; D005462:Fluorine Radioisotopes; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D019275:Radiopharmaceuticals; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013440:Sulfides