Development of LC-MS/MS-Based Receptor Occupancy Tracers and Positron Emission Tomography Radioligands for the Nociceptin/Orphanin FQ (NOP) Receptor

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...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2012-06, Vol.55 (11), p.4955-4967
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Brain - diagnostic imaging
Brain - metabolism
Carbon Radioisotopes
CHO Cells
Chromatography, Liquid
Cricetinae
Cricetulus
HEK293 Cells
Humans
Macaca
Male
Narcotic Antagonists
Positron-Emission Tomography
Radioligand Assay
Radiopharmaceuticals - chemical synthesis
Radiopharmaceuticals - chemistry
Radiopharmaceuticals - pharmacokinetics
Rats
Rats, Sprague-Dawley
Receptors, Opioid - agonists
Receptors, Opioid - metabolism
Spiro Compounds - chemical synthesis
Spiro Compounds - chemistry
Spiro Compounds - pharmacokinetics
Stereoisomerism
Structure-Activity Relationship
Tandem Mass Spectrometry
Thiophenes - chemical synthesis
Thiophenes - chemistry
Thiophenes - pharmacokinetics
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm201629q