Journal of Medicinal Chemistry p. 4955 - 4967 (2012)
Update date:2022-07-29
Topics:
Pedregal, Concepción
Joshi, Elizabeth M.
Toledo, Miguel A.
Lafuente, Celia
Diaz, Nuria
Martinez-Grau, Maria A.
Jiménez, Alma
Benito, Ana
Navarro, Antonio
Chen, Zhaogen
Mudra, Daniel R.
Kahl, Steven D.
Rash, Karen S.
Statnick, Michael A.
Barth, Vanessa N.
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 [11C]-(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 [11C]-(S)-30 is being evaluated as a PET radiotracer for the NOP receptor in human subjects.
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(2012)