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

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• 作者：Victor W. Pike ; Karen S. Rash ; Zhaogen Chen ; Concepcio虂n Pedregal ; Michael A. Statnick ; Yasuyuki Kimura ; Jinsoo Hong ; Sami S. Zoghbi ; Masahiro Fujita ; Miguel A. Toledo ; Nuria Diaz ; Susan L. Gackenheimer ; Johannes T. Tauscher ; Vanessa N. Barth ; Robert B. Innis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 28, 2011
• 年：2011
• 卷：54
• 期：8
• 页码：2687-2700
• 全文大小：1119K
• 年卷期：v.54,no.8(April 28, 2011)
• ISSN：1520-4804

文摘

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鈥?fluoro-4鈥?5鈥?dihydrospiro[piperidine-4,7鈥?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鈭?b>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.