Synthesis, In Vitro and In Vivo Evaluation, and Radiolabeling of Aryl Anandamide Analogues as Candidate Radioligands for In Vivo Imaging of Fatty Acid Amide Hydrolase in the Brain

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• 作者：Leonie wyffels ; Giulio G. Muccioli ; Sylvie De Bruyne ; Lieselotte Moerman ; Johan Sambre ; Didier M. Lambert ; Filip De Vos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：August 13, 2009
• 年：2009
• 卷：52
• 期：15
• 页码：4613-4622
• 全文大小：892K
• 年卷期：v.52,no.15(August 13, 2009)
• ISSN：1520-4804

文摘

Fatty acid amide hydrolyase (FAAH) is one of the main enzymes responsible for terminating the signaling of endocannabinoids in the brain. Imaging FAAH in vivo using PET or SPECT is important to deeper understanding of its role in neuropsychiatric disorders. However, at present, no radioligand is available for mapping the enzyme in vivo. Here, we synthesized 18 aryl analogues of anandamide, FAAH’s endogenous substrate, and in vitro evaluated their potential as metabolic trapping tracers. Interaction studies with recombinant FAAH revealed good to very good interaction of the methoxy substituted aryl anandamide analogues 17, 18, 19, and 20 with FAAH and they were identified as competing substrates. Compounds 17 and 18 did not display significant binding to CB₁ and CB₂ cannabinoid receptors and stand out as potential candidate metabolic trapping tracers. They were successfully labeled with ¹¹C in good yields and high radiochemical purity and displayed brain uptake in C57BL/6J mice. Radioligands [¹¹C]-17 and [¹¹C]-18 merit further investigation in vivo.