title: Development of fluorinated CB(2) receptor agonists for PET studies.
abstract: A convergent strategy was followed to modify systematically carbazole based CB(2) receptor ligands. The length of the N-(fluoroalkyl) group (n in 7), the length of the alkanamide (m in 7) and the substitution pattern of the phenyl moiety (X and Y in 7) were varied systematically. The highest CB(2) affinity was found for the 2-fluoroethyl substituted carbazole derivative 20a (Ki=5.8nM) containing the propionamide and the 2-bromo-4-fluorophenyl moiety. According to docking studies 20a fits nicely into the binding pocket of the CB(2) receptor, but elongation of the fluoroethyl side chain leads to a different binding mode of the ligands. The high CB(2) affinity together with the high selectivity over the CB(2) subtype qualifies the fluoroethyl derivative 20a to be developed as a PET tracer.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
authors.forename: Corinna
authors.initials: C
authors.lastname: Lueg
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Robert
authors.initials: R
authors.lastname: Günther
authors.forename: Peter
authors.initials: P
authors.lastname: Brust
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D016466:CHO Cells; D002227:Carbazoles / Q000737:chemistry* / Q000494:pharmacology*; D003412:Cricetulus; D054879:Halogenation; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D049268:Positron-Emission Tomography; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists* / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D002227:Carbazoles; D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; C041514:carbazole
keywords: CB(2) receptor ligands; Carbazole derivatives; Docking; Fluorinated ligands; PET; Structure affinity relationships