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.

Autor: Huang YY; PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, Taiwan., Chang LT; School of Pharmacy, College of Medicine, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan., Shen HY; School of Pharmacy, College of Medicine, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan., Chen YH; School of Pharmacy, College of Medicine, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan., Tzen KY; PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, Taiwan., Shiue CY; PET Center, Department of Nuclear Medicine, National Taiwan University Hospital, 7, Chung-Shan S. Road, Taipei, Taiwan. Electronic address: shiue@ntuh.gov.tw., Hsin LW; School of Pharmacy, College of Medicine, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan; Center for Innovative Therapeutics Discovery, National Taiwan University, 17, Xuzhou Road, Room 936, Taipei 10055, Taiwan. Electronic address: lwhsin@ntu.edu.tw.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Apr; Vol. 97, pp. 103654. Date of Electronic Publication: 2020 Feb 06.
DOI: 10.1016/j.bioorg.2020.103654
Abstrakt: 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. [ 18 F]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, [ 18 F]7a exhibited the highest uptake in the midbrain, whereas [ 18 F]7b exhibited the highest uptake in the hypothalamus and midbrain. After treatment with citalopram, a SERT-selective ligand, the uptake of [ 18 F]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 [ 18 F]7a is a promising lead for the further development of novel [ 18 F]-labeled PET imaging agents for SERT binding sites in the brain.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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