title: Design, synthesis, and binding affinities of potential positron emission tomography (PET) ligands for visualization of brain dopamine D3 receptors.
abstract: We here report the synthesis of compounds structurally related to the high-affinity dopamine D(3) receptor ligand N-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl]-7-methoxy-2-benzofurancarboxamide (1). All compounds were specifically designed as potential PET radioligands for brain D(3) receptors visualization, having lipophilicity within a range for high brain uptake and weak nonspecific binding (2 < ClogP < 3.5) and bearing a methoxy substituent for easy access to labeling with the positron emitter isotope (11)C. N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(4-morpholinyl)benzamide (22), N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-4-(1H-imidazol-1-yl)benzamide (23), and N-[4-[4-(5-methoxy-2-benzisoxazolyl)piperazin-1-yl]butyl]-5-(2-furanyl)-1H-pyrazole-3-carboxamide (24) displayed good D(3) receptor affinities (K(i) values 38.0, 22.6, and 21.3 nM, respectively) and were selective over D(2) receptor. Moreover, compounds 22-24 were able to permeate the Caco-2 cell monolayer, differently from compound 1. Although the goal to identify potential PET radioligands with subnanomolar affinities for D(3) receptor was not achieved, the proposed strategy could be a starting point for future developments.
authors.affiliation: Università degli Studi di Bari, Dipartimento Farmaco-Chimico, via Orabona, 4, 70125 Bari, Italy. leopoldo@farmchim.uniba.it
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
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: Mauro
authors.initials: M
authors.lastname: Niso
authors.forename: Francesco
authors.initials: F
authors.lastname: Berardi
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018938:Caco-2 Cells; D015195:Drug Design; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001572:Benzofurans; D008024:Ligands; C470206:N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-7-methoxy-2-benzofurancarboxamide; D010879:Piperazines; D050637:Receptors, Dopamine D3