1283095-70-4

Upstream product

• 1283095-64-6 (2S)-2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)propanamide 
• 74-88-4 methyl iodide 
• 1283095-51-1 t-butyl 3-(2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]-1'-yl)propanoate 
• 1283095-50-0 2-fluorospiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine] 
• 1283095-48-6 tert-butyl-4′,5′-dihydro-1H-spiro[piperidine-4,7′-thieno[2,3-c]pyran]-1-carboxylate 
• 1283095-61-3 2-[(2-fluorophenyl)methyl]-3-(2-fluorospiro[4,5-dihydrothieno-[2,3-c]pyran-7,4'-piperidine]-1'-yl)-N-methylpropanamide 
• 1283095-47-5 4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] 
• 13781-67-4 3-(2-hydroxyethyl)thiophene 

Relevant academic research and scientific papers

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 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.

Synthesis and evaluation of radioligands for imaging brain nociceptin/orphanin FQ peptide (NOP) receptors with positron emission tomography

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.