title: Development of LC-MS/MS-based receptor occupancy tracers and positron emission tomography radioligands for the nociceptin/orphanin FQ (NOP) receptor.
abstract: Currently, a lack of sufficient tools has limited the understanding of the relationship between neuropsychiatric disorders and the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor. Herein, we describe the discovery and development of an antagonist NOP receptor occupancy (RO) tracer and a novel positron emission tomography (PET) radioligand suitable to probe the NOP receptor in human clinical studies. A thorough structure-activity relationship (SAR) around the high-affinity 3-(2'-fluoro-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]-1-yl)-2-(2-halobenzyl)-N-alkylpropanamide scaffold identified a series of subnanomolar, highly selective NOP antagonists. Subsequently, these unlabeled NOP ligands were evaluated in vivo by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in rat to determine brain uptake, kinetics and specific binding. (S)-27 was identified as a suitable unlabeled preclinical RO tracer to accurately quantify NOP receptor engagement in rat brain. Three compounds were selected for evaluation in nonhuman primates as PET tracers: (-)-26, (-)-30, and (-)-33. Carbon-11 labeling of (+)-31 yielded [(11)C]-(S)-30, which exhibited minimal generation of central nervous system (CNS) penetrant radiometabolites, improved brain uptake, and was an excellent PET radioligand in both rat and monkey. Currently [(11)C]-(S)-30 is being evaluated as a PET radiotracer for the NOP receptor in human subjects.
authors.affiliation: Centro de Investigación Lilly, Avenida de la Industria 30, 28108-Alcobendas, Madrid, Spain. conchipe@lilly.com
authors.forename: Concepción
authors.initials: C
authors.lastname: Pedregal
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Joshi
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Toledo
authors.forename: Celia
authors.initials: C
authors.lastname: Lafuente
authors.forename: Nuria
authors.initials: N
authors.lastname: Diaz
authors.forename: Maria A
authors.initials: MA
authors.lastname: Martinez-Grau
authors.forename: Alma
authors.initials: A
authors.lastname: Jiménez
authors.forename: Ana
authors.initials: A
authors.lastname: Benito
authors.forename: Antonio
authors.initials: A
authors.lastname: Navarro
authors.forename: Zhaogen
authors.initials: Z
authors.lastname: Chen
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.forename: Steven D
authors.initials: SD
authors.lastname: Kahl
authors.forename: Karen S
authors.initials: KS
authors.lastname: Rash
authors.forename: Michael A
authors.initials: MA
authors.lastname: Statnick
authors.forename: Vanessa N
authors.initials: VN
authors.lastname: Barth
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D016466:CHO Cells; D002250:Carbon Radioisotopes; D002853:Chromatography, Liquid; D006224:Cricetinae; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D008251:Macaca; D008297:Male; D009292:Narcotic Antagonists; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D053719:Tandem Mass Spectrometry; D013876:Thiophenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000094942:Nociceptin Receptor
chemical_list: C575270:2-((2-fluorophenyl)methyl)-3-(2-fluorospiro(4,5-dihydrothieno(2,3-c)pyran-7,4'-piperidine)-1'-yl)-N-methylpropanamide; D002250:Carbon Radioisotopes; D009292:Narcotic Antagonists; D019275:Radiopharmaceuticals; D011957:Receptors, Opioid; D013141:Spiro Compounds; D013876:Thiophenes; D000094942:Nociceptin Receptor