Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography

J Med Chem. 2011 Apr 28;54(8):2687-700. doi: 10.1021/jm101487v. Epub 2011 Mar 25.


Positron emission tomography (PET) coupled to an effective radioligand could provide an important tool for understanding possible links between neuropsychiatric disorders and brain NOP (nociceptin/orphanin FQ peptide) receptors. We sought to develop such a PET radioligand. High-affinity NOP ligands were synthesized based on a 3-(2'-fluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)-2(2-halobenzyl)-N-alkylpropanamide scaffold and from experimental screens in rats, with ex vivo LC-MS/MS measures, three ligands were identified for labeling with carbon-11 and evaluation with PET in monkey. Each ligand was labeled by (11)C-methylation of an N-desmethyl precursor and studied in monkey under baseline and NOP receptor-preblock conditions. The three radioligands, [(11)C](S)-10a-c, gave similar results. Baseline scans showed high entry of radioactivity into the brain to give a distribution reflecting that expected for NOP receptors. Preblock experiments showed high early peak levels of brain radioactivity, which rapidly declined to a much lower level than seen in baseline scans, thereby indicating a high level of receptor-specific binding in baseline experiments. Overall, [(11)C](S)-10c showed the most favorable receptor-specific signal and kinetics and is now selected for evaluation in human subjects.

Publication types

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

MeSH terms

  • Animals
  • Brain / diagnostic imaging*
  • Chromatography, Liquid
  • Haplorhini
  • Magnetic Resonance Spectroscopy
  • Opioid Peptides / metabolism*
  • Positron-Emission Tomography
  • Radioligand Assay
  • Rats
  • Stereoisomerism
  • Tandem Mass Spectrometry


  • Opioid Peptides
  • nociceptin