Click chemistry based synthesis of dopamine D4 selective receptor ligands for the selection of potential PET tracers

Bioorg Med Chem Lett. 2013 Nov 15;23(22):6079-82. doi: 10.1016/j.bmcl.2013.09.026. Epub 2013 Sep 17.


Taking advantage of click chemistry, a library of N-arylpiperazinylmethyl triazoles bearing fluoro substituted appendages was synthesized and the target compounds were investigated for dopamine and serotonin receptor binding. With the aim to bias their hydrophilicity and to optimize their D4 receptor affinity and selectivity, a concise series of triazoles containing fluoroalkyl, fluoroalkoxy, fluoroalkoxyphenyl, and deoxyfluoroglucosyl substituents was studied. The D4 receptor affinity and selectivity could be tuned by altering the chemical moiety attached to the triazole unit. Among the test compounds, the fluoroethoxyphenyl derivative 15b showed weak partial agonism at D4 and a K(i) value of 14 nM, while its fluoropropoxyphenyl homologue 16a turned out to act as a neutral D4 antagonist (K(i)=5.1 nM). Both, 15b and 16a revealed an excellent balance between D4 receptor affinity and subtype selectivity, providing lead candidates for the development of (18)F-labeled radioligands for D4 receptor imaging studies by positron emission tomography (PET).

Keywords: Click chemistry; D4 receptor; Dopamine; Fluorine; PET; Triazole.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes / chemical synthesis
  • Alkynes / chemistry
  • Click Chemistry / methods
  • Humans
  • Hydrocarbons, Fluorinated / chemical synthesis
  • Hydrocarbons, Fluorinated / chemistry
  • Ligands
  • Molecular Structure
  • Piperazines / chemical synthesis
  • Piperazines / chemistry
  • Positron-Emission Tomography / methods*
  • Radioligand Assay
  • Receptors, Dopamine D4 / chemistry*
  • Receptors, Dopamine D4 / metabolism
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry


  • Alkynes
  • Hydrocarbons, Fluorinated
  • Ligands
  • Piperazines
  • Triazoles
  • Receptors, Dopamine D4