Synthesis, Structure-Affinity Relationships, and Radiolabeling of Selective High-Affinity 5-HT4 Receptor Ligands as Prospective Imaging Probes for Positron Emission Tomography

J Med Chem. 2010 Oct 14;53(19):7035-47. doi: 10.1021/jm100668r.


In a search for high-affinity receptor ligands that might serve for development as radioligands for the imaging of brain 5-HT(4) receptors in vivo with positron emission tomography (PET), structural modifications were made to the high-affinity 5-HT(4) antagonist (1-butylpiperidin-4-yl)methyl 8-amino-7-iodo-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate (1, SB 207710). These modifications were made mainly on the aryl side of the ester bond to permit possible rapid labeling of the carboxylic acid component with a positron emitter, either carbon-11 (t(1/2) = 20.4 min) or fluorine-18 (t(1/2) = 109.7 min), and included (i) replacement of the iodine atom with a small substituent such as nitrile, methyl, or fluoro, (ii) methylation of the 8-amino group, (iii) opening of the dioxan ring, and (iv) alteration of the length of the N-alkyl goup. High-affinity ligands were discovered for recombinant human 5-HT(4) receptors with amenability to labeling with a positron emitter and potential for development as imaging probes. The ring-opened radioligand, (([methoxy-(11)C]1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate; [(11)C]13), showed an especially favorable array of properties for future evaluation as a PET radioligand for brain 5-HT(4) receptors.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 4-Aminobenzoic Acid / chemical synthesis
  • 4-Aminobenzoic Acid / chemistry
  • 4-Aminobenzoic Acid / metabolism
  • Animals
  • Brain / diagnostic imaging
  • Brain / metabolism
  • Carbon Radioisotopes
  • Cell Line
  • Cricetinae
  • Drug Inverse Agonism
  • Drug Partial Agonism
  • Fluorine Radioisotopes
  • Guinea Pigs
  • Humans
  • Isotope Labeling
  • Ligands
  • Positron-Emission Tomography
  • Radiopharmaceuticals / chemical synthesis*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / metabolism
  • Rats
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Serotonin 5-HT4 Receptor Agonists
  • Serotonin 5-HT4 Receptor Antagonists*
  • Species Specificity
  • Structure-Activity Relationship
  • para-Aminobenzoates*


  • (1-butylpiperidin-4-yl)methyl 4-amino-3-methoxybenzoate
  • Carbon Radioisotopes
  • Fluorine Radioisotopes
  • Ligands
  • Radiopharmaceuticals
  • Serotonin 5-HT4 Receptor Agonists
  • Serotonin 5-HT4 Receptor Antagonists
  • para-Aminobenzoates
  • Receptors, Serotonin, 5-HT4
  • 4-Aminobenzoic Acid