Design, synthesis, lipophilic properties, and binding affinities of potential ligands in positron emission tomography (PET) for visualization of brain dopamine D4 receptors

Chem Biodivers. 2014 Feb;11(2):299-310. doi: 10.1002/cbdv.201300194.

Abstract

We report the synthesis of compounds structurally related to the high-affinity dopamine D4 receptor ligand N-{2-[4-(3-cyanopyridin-2-yl)piperazin-1-yl]ethyl}-3-methoxybenzamide (1e). All compounds were specifically designed as potential PET radioligands for brain D4 receptor visualization, having lipophilicity within a range for brain uptake and weak non-specific binding (0.75<cLogP<3.15) and bearing a substituent for easy access to labeling with the positron emitter isotope (11) C or (18) F. The best compound of the series, N-{2-[4-(4-chlorophenyl)piperazin-1-yl]ethyl}-6-fluoropyridine-3-carboxamide (7a), displayed excellent selectivity over D2 and D3 receptors (>100-fold), but its D4 receptor affinity was suboptimal for imaging of brain D4 receptors (Ki =30 nM).

Keywords: Dopamine D4 receptors; G-Protein-coupled receptors (GPCR); Piperazine, 1-aryl-; Positron Emission Tomography (PET); Structureactivity relationships (SAR); cLogP.

MeSH terms

  • Animals
  • Benzamides* / chemical synthesis
  • Benzamides* / chemistry
  • Binding Sites / drug effects
  • Brain / metabolism*
  • CHO Cells
  • Cricetulus
  • Drug Design*
  • Humans
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Piperazines* / chemical synthesis
  • Piperazines* / chemistry
  • Positron-Emission Tomography*
  • Rats
  • Receptors, Dopamine D4 / chemistry
  • Receptors, Dopamine D4 / metabolism*
  • Tumor Cells, Cultured

Substances

  • Benzamides
  • Ligands
  • N-(2-(4-(3-cyanopyridin-2-yl)piperazin-1-yl)ethyl)-3-methoxybenzamide
  • Piperazines
  • Receptors, Dopamine D4