Discovery of novel α₁-adrenoceptor ligands based on the antipsychotic sertindole suitable for labeling as PET ligands

Bioorg Med Chem. 2013 Jan 1;21(1):196-204. doi: 10.1016/j.bmc.2012.10.049. Epub 2012 Nov 15.

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.

MeSH terms

  • Animals
  • Antipsychotic Agents / chemistry*
  • Antipsychotic Agents / metabolism
  • Antipsychotic Agents / pharmacokinetics*
  • Brain / diagnostic imaging
  • Brain / metabolism*
  • CHO Cells
  • Caco-2 Cells
  • Cricetinae
  • Humans
  • Imidazoles / chemistry*
  • Imidazoles / metabolism
  • Imidazoles / pharmacokinetics*
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacokinetics*
  • Ligands
  • Positron-Emission Tomography
  • Rats
  • Receptors, Adrenergic, alpha-1 / metabolism*

Substances

  • Antipsychotic Agents
  • Imidazoles
  • Indoles
  • Ligands
  • Receptors, Adrenergic, alpha-1
  • sertindole