Details

Autor(en) / Beteiligte

• Joergensen, Morten
• Joergensen, Pernille N
• Christoffersen, Claus T
• Jensen, Klaus G
• Balle, Thomas
• Bang-Andersen, Benny

Titel

Discovery of novel [alpha]1-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands

Ist Teil von

• Bioorganic & medicinal chemistry, 2013-01, Vol.21 (1), p.196-204

Erscheinungsjahr

2013

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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)-1 H -indole (Lu AA27122, 3i) and 1-(4-fluorophenyl)-5-(1-methyl-1H-1,2,4-triazol-3-yl)-3-(1-methylp i peridin-4-yl)-1H-indole (3l) were identified as high affinity [alpha]1A-adrenoceptor ligands with Ki values of 0.52 and 0.16 nM, respectively, and with a >100-fold selectivity versus dopamine D2 receptors. Compound 3i showed almost equal affinity for [alpha]1B- (Ki = 1.9 nM) and [alpha]1D-adrenoceptors (Ki = 2.5 nM) as for [alpha]1A, as well as moderate affinity for 5-HT1B (Ki = 13 nM) and 5-HT6 (Ki = 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.