Synthesis and Preliminary Evaluation of N-(16-18F-Fluorohexadecanoyl)ethanolamine (18F-FHEA) as a PET Probe of N-Acylethanolamine Metabolism in Mouse Brain

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• 作者：Mukesh K. Pandey ; Timothy R. DeGrado ; Kun Qian ; Mark S. Jacobson ; Clinton E. Hagen ; Richard I. Duclos ; Jr. ; S. John Gatley
• 刊名：ACS Chemical Neuroscience
• 出版年：2014
• 出版时间：September 17, 2014
• 年：2014
• 卷：5
• 期：9
• 页码：793-802
• 全文大小：366K
• ISSN：1948-7193

文摘

N-Acylethanolamines are lipid signaling molecules found throughout the plant and animal kingdoms. The best-known mammalian compound of this class is anandamide, N-arachidonoylethanolamine, one of the endogenous ligands of cannabinoid CB1 and CB2 receptors. Signaling by N-acylethanolamines is terminated by release of the ethanolamine moiety by hydrolyzing enzymes such as fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing amidase (NAAA). Herein, we report the design and synthesis of N-(16-p>18p>F-fluorohexadecanoyl)ethanolamine (p>18p>F-FHEA) as a positron emission tomography (PET) probe for imaging the activity of N-acylethanolamine hydrolyzing enzymes in the brain. Following intravenous administration of p>18p>F-FHEA in Swiss Webster mice, p>18p>F-FHEA was extracted from blood by the brain and underwent hydrolysis at the amide bond and incorporation of the resultant p>18p>F-fluorofatty acid into complex lipid pools. Pretreatment of mice with the FAAH inhibitor URB-597 (1 mg/kg IP) resulted in significantly slower p>18p>F-FHEA incorporation into lipid pools, but overall p>18p>F concentrations in brain regions were not altered. Likewise, pretreatment with a NAAA inhibitor, (S)-N-(2-oxo-3-oxytanyl)biphenyl-4-carboxamide (30 mg/kg IV), did not significantly affect the uptake of p>18p>F-FHEA in the brain. Although evidence was found that p>18p>F-FHEA behaves as a substrate of FAAH in the brain, the lack of sensitivity of brain uptake kinetics to FAAH inhibition discourages its use as a metabolically trapped PET probe of N-acylethanolamine hydrolyzing enzyme activity.

Keywords:

Endocannabinoids; N-acylethanolamines; N-(16-p>18p>F-fluorohexadecanoyl)ethanolamine; p>18p>F-FHEA; PET