title: Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography.
abstract: 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.
authors: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, United States. pikev@mail.nih.gov
authors: Victor W
authors: VW
authors: Pike
authors: Karen S
authors: KS
authors: Rash
authors: Zhaogen
authors: Z
authors: Chen
authors: Concepción
authors: C
authors: Pedregal
authors: Michael A
authors: MA
authors: Statnick
authors: Yasuyuki
authors: Y
authors: Kimura
authors: Jinsoo
authors: J
authors: Hong
authors: Sami S
authors: SS
authors: Zoghbi
authors: Masahiro
authors: M
authors: Fujita
authors: Miguel A
authors: MA
authors: Toledo
authors: Nuria
authors: N
authors: Diaz
authors: Susan L
authors: SL
authors: Gackenheimer
authors: Johannes T
authors: JT
authors: Tauscher
authors: Vanessa N
authors: VN
authors: Barth
authors: Robert B
authors: RB
authors: Innis
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging*; D002853:Chromatography, Liquid; D000882:Haplorhini; D009682:Magnetic Resonance Spectroscopy; D018847:Opioid Peptides / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D051381:Rats; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry; D000097629:Nociceptin
chemical_list: D018847:Opioid Peptides; D000097629:Nociceptin