Discovery of MK-3168: A PET Tracer for Imaging Brain Fatty Acid Amide Hydrolase

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• 作者：Ping Liu ; Terence G. Hamill ; Marc Chioda ; Harry Chobanian ; Selena Fung ; Yan Guo ; Linda Chang ; Raman Bakshi ; Qingmei Hong ; James Dellureficio ; Linus S. Lin ; Catherine Abbadie ; Jessica Alexander ; Hong Jin ; Suzanne Mandala ; Lin-Lin Shiao ; Wenping Li ; Sandra Sanabria ; David Williams ; Zhizhen Zeng ; Richard Hajdu ; Nina Jochnowitz ; Mark Rosenbach ; Bindhu Karanam ; Maria Madeira ; Gino Salituro ; Joyce Powell ; Ling Xu ; Jenna L. Terebetski ; Joseph F. Leone ; Patricia Miller ; Jacquelynn Cook ; Marie Holahan ; Aniket Joshi ; Stacey O鈥橫alley ; Mona Purcell ; Diane Posavec ; Tsing-Bau Chen ; Kerry Riffel ; Mangay Williams ; Richard Hargreaves ; Kathleen A. Sullivan ; Ravi P. Nargund ; Robert J. DeVita
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：June 13, 2013
• 年：2013
• 卷：4
• 期：6
• 页码：509-513
• 全文大小：310K
• 年卷期：v.4,no.6(June 13, 2013)
• ISSN：1948-5875

文摘

We report herein the discovery of a fatty acid amide hydrolase (FAAH) positron emission tomography (PET) tracer. Starting from a pyrazole lead, medicinal chemistry efforts directed toward reducing lipophilicity led to the synthesis of a series of imidazole analogues. Compound 6 was chosen for further profiling due to its appropriate physical chemical properties and excellent FAAH inhibition potency across species. [¹¹C]-6 (MK-3168) exhibited good brain uptake and FAAH-specific signal in rhesus monkeys and is a suitable PET tracer for imaging FAAH in the brain.

Keywords:

Fatty acid amide hydrolase; FAAH; positron emission tomography; carbon-11; PET tracer; target engagement; biomarker