Synthesis and Evaluation of Radioligands for Imaging Brain Nociceptin/Orphanin FQ Peptide (NOP) Receptors with Positron Emission Tomography

• Published in: Journal of medicinal chemistry Vol. 54; no. 8; pp. 2687 - 2700
• Main Authors: Pike, Victor W, Rash, Karen S, Chen, Zhaogen, Pedregal, Concepción, Statnick, Michael A, Kimura, Yasuyuki, Hong, Jinsoo, Zoghbi, Sami S, Fujita, Masahiro, Toledo, Miguel A, Diaz, Nuria, Gackenheimer, Susan L, Tauscher, Johannes T, Barth, Vanessa N, Innis, Robert B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.04.2011; Amer Chemical Soc
• Subjects: Animals; Brain - diagnostic imaging; Chemistry, Medicinal; Chromatography, Liquid; Haplorhini; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Nociceptin; Opioid Peptides - metabolism; Pharmacology & Pharmacy; Positron-Emission Tomography; Radioligand Assay; Rats; Science & Technology; Stereoisomerism; Tandem Mass Spectrometry; AUTORADIOGRAPHIC LOCALIZATION; ORPHANIN-FQ; ANTAGONIST SB-612111; OPIOID RECEPTOR; PHARMACOLOGICAL CHARACTERIZATION; IN-VIVO; DOPAMINE D2; BINDING-SITES; RADIOTRACERS; OCCUPANCY
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm101487v

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 11C-methylation of an N-desmethyl precursor and studied in monkey under baseline and NOP receptor-preblock conditions. The three radioligands, [11C]( 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, [11C]( S )-10c showed the most favorable receptor-specific signal and kinetics and is now selected for evaluation in human subjects.