title: Design, synthesis, lipophilic properties, and binding affinities of potential ligands in positron emission tomography (PET) for visualization of brain dopamine D4 receptors.
abstract: We report the synthesis of compounds structurally related to the high-affinity dopamine D4 receptor ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non-specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope (11) C or (18) F. The best compound of the series, N-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-6-fluoropyridine-3-carboxamide (7a), displayed excellent selectivity over D2 and D3 receptors (>100-fold), but its D4 receptor affinity was suboptimal for imaging of brain D4 receptors (Ki =30 nM).
authors.affiliation: Dipartimento di Farmacia - Scienze del Farmaco, Università degli Studi di Bari Aldo Moro, via Orabona, 4, IT-70125, Bari, (phone +39 080 544 2798; fax +39 080 544 2231).
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.forename: Paola
authors.initials: P
authors.lastname: De Giorgio
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry; D049268:Positron-Emission Tomography; D051381:Rats; D050638:Receptors, Dopamine D4 / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D008024:Ligands; C553262:N-(2-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)ethyl)-3-methoxybenzamide; D010879:Piperazines; D050638:Receptors, Dopamine D4
keywords: Dopamine D4 receptors; G-Protein-coupled receptors (GPCR); Piperazine, 1-aryl-; Positron Emission Tomography (PET); Structureactivity relationships (SAR); cLogP