Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers

J Med Chem. 2012 Nov 26;55(22):9693-707. doi: 10.1021/jm300943r. Epub 2012 Nov 9.


The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to an increase of both the affinity and selectivity for 5-HT(4)R, suggesting the design of the antagonist 4v, exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dioxanes / pharmacology*
  • Drug Design*
  • Humans
  • Iodine Radioisotopes*
  • Ligands
  • Mice
  • Molecular Probes
  • Piperidines / pharmacology*
  • Radioligand Assay
  • Radiopharmaceuticals
  • Receptors, Serotonin, 5-HT4 / chemistry*
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Serotonin 5-HT4 Receptor Antagonists / chemical synthesis*
  • Serotonin 5-HT4 Receptor Antagonists / pharmacology
  • Structure-Activity Relationship
  • Tomography, Emission-Computed, Single-Photon*


  • Dioxanes
  • Iodine Radioisotopes
  • Ligands
  • Molecular Probes
  • Piperidines
  • Radiopharmaceuticals
  • SB 207710
  • Serotonin 5-HT4 Receptor Antagonists
  • Receptors, Serotonin, 5-HT4