title: 18F-Labeled FAUC 346 and BP 897 derivatives as subtype-selective potential PET radioligands for the dopamine D3 receptor.
abstract: Disturbances of neutrotransmission at the dopamine D3 receptor are related to several neuropsychiatric diseases and in particular to drug addiction. Herein, we report the computer-assisted prediction of D3 selectivities of new fluoroalkoxy-substituted receptor ligands by means of 3D-QSAR analysis. As close analogues of the D3-selective lead compound FAUC 346 and BP 879, the (19)F-substituted test compounds 4 a-d were synthesized and evaluated. In vitro investigation of their binding characteristics in transfected Chinese Hamster Ovary (CHO) cells led to excellent K(i) values between 0.12 and 0.69 nM at the dopamine D3 subtype. The benzothiophene-substituted carboxamide 4 a (K(i)=0.12 nM) displayed 133 and 283-fold selectivity over the structurally related D2(Long) and D4 subtypes, respectively. Mitogenesis assays showed the behavior of partial agonists. Based on these data, we synthesized the [(18)F]fluoroethoxy-substituted radioligands [(18)F]4 a-d. The N-[4-[4-(2-hydroxyphenyl)piperazin-1-yl]butyl]-2-carboxamides 3 a-d were prepared and labeled with 2-[(18)F]fluoroethyltosylate in a two-step procedure. Optimization of the (18)F-labeling conditions led to radiochemical yields between 24 and 65 %.
authors.affiliation: Clinic of Nuclear Medicine, Friedrich-Alexander University, Krankenhausstrasse 12, 91054 Erlangen, Germany. carsten.hocke@nuklear.imed.uni-erlangen.de
authors.forename: Carsten
authors.initials: C
authors.lastname: Hocke
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
authors.forename: Ismael
authors.initials: I
authors.lastname: Salama
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
mesh_terms: D005462:Fluorine Radioisotopes; D006801:Humans; D007553:Isotope Labeling; D010879:Piperazines / Q000378:metabolism*; D049268:Positron-Emission Tomography; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D050637:Receptors, Dopamine D3 / Q000032:analysis*; D013876:Thiophenes / Q000378:metabolism*
chemical_list: C467222:FAUC 346; D005462:Fluorine Radioisotopes; D010879:Piperazines; D019275:Radiopharmaceuticals; D050637:Receptors, Dopamine D3; D013876:Thiophenes; C120565:BP 897