title: Discovery of novel α₁-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands.
abstract: The synthesis and in vitro preclinical profile of a series of 5-heteroaryl substituted analogs of the antipsychotic drug sertindole are presented. Compounds 1-(4-fluorophenyl)-3-(1-methylpiperidin-4-yl)-5-(pyrimidin-5-yl)-1H-indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylpiperidin-4-yl)-1H-indole (3l) were identified as high affinity α(1A)-adrenoceptor ligands with K(i) values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D(2) receptors. Compound 3i showed almost equal affinity for α(1B)- (K(i)=1.9 nM) and α(1D)-adrenoceptors (K(i)=2.5 nM) as for α(1A), as well as moderate affinity for 5-HT(1B) (K(i)=13 nM) and 5-HT(6) (K(i)=16 nM) receptors, whereas 3l showed >40-fold selectivity toward all other targets tested. Based on in vitro assays for assessment of permeability rates and extent, it is predicted that both compounds enter the brain of rats, non-human primates, as well as humans, and as such are good candidates to be carried forward for further evaluation as positron emission tomography (PET) ligands.
authors.affiliation: Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Copenhagen-Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Jørgensen
authors.forename: Pernille N
authors.initials: PN
authors.lastname: Jørgensen
authors.forename: Claus T
authors.initials: CT
authors.lastname: Christoffersen
authors.forename: Klaus G
authors.initials: KG
authors.lastname: Jensen
authors.forename: Thomas
authors.initials: T
authors.lastname: Balle
authors.forename: Benny
authors.initials: B
authors.lastname: Bang-Andersen
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D016466:CHO Cells; D018938:Caco-2 Cells; D006224:Cricetinae; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D007211:Indoles / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics*; D008024:Ligands; D049268:Positron-Emission Tomography; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*
chemical_list: D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D008024:Ligands; D018340:Receptors, Adrenergic, alpha-1; C066304:sertindole