Abstract
N-Acylethanolamines are lipid signaling molecules found throughout the plant and animal kingdoms. The best-known mammalian compound of this class is anandamide, Narachidonoylethanolamine, 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-(16-18F-fluorohexadecanoyl)- ethanolamine (18F-FHEA) as a positron emission tomography (PET) probe for imaging the activity of N-acylethanolamine hydrolyzing enzymes in the brain. Following intravenous administration of 18F-FHEA in Swiss Webster mice, 18F-FHEA was extracted from blood by the brain and underwent hydrolysis at the amide bond and incorporation of the resultant 18F-fluorofatty acid into complex lipid pools. Pretreatment of mice with the FAAH inhibitor URB-597 (1 mg/kg IP) resulted in significantly slower 18F-FHEA incorporation into lipid pools, but overall 18F 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 18F-FHEA in the brain. Although evidence was found that 18F-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. (Chemical Equation Presented).
| Original language | English (US) |
|---|---|
| Pages (from-to) | 793-802 |
| Number of pages | 10 |
| Journal | ACS Chemical Neuroscience |
| Volume | 5 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 17 2014 |
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Keywords
- F-FHEA
- Endocannabinoids
- N-(16-F-fluorohexadecanoyl)ethanolamine
- N-acylethanolamines
- PET
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Physiology
- Cognitive Neuroscience
Cite this
Synthesis and preliminary evaluation of N-(16-18F-fluorohexadecanoyl) ethanolamine (18F-FHEA) as a PET probe of N-acylethanolamine metabolism in mouse brain. / Pandey, Mukesh; DeGrado, Timothy R; Qian, Kun; Jacobson, Mark S.; Hagen, Clinton E.; Duclos, Richard I.; Gatley, S. John.
In: ACS Chemical Neuroscience, Vol. 5, No. 9, 17.09.2014, p. 793-802.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis and preliminary evaluation of N-(16-18F-fluorohexadecanoyl) ethanolamine (18F-FHEA) as a PET probe of N-acylethanolamine metabolism in mouse brain
AU - Pandey, Mukesh
AU - DeGrado, Timothy R
AU - Qian, Kun
AU - Jacobson, Mark S.
AU - Hagen, Clinton E.
AU - Duclos, Richard I.
AU - Gatley, S. John
PY - 2014/9/17
Y1 - 2014/9/17
N2 - N-Acylethanolamines are lipid signaling molecules found throughout the plant and animal kingdoms. The best-known mammalian compound of this class is anandamide, Narachidonoylethanolamine, 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-(16-18F-fluorohexadecanoyl)- ethanolamine (18F-FHEA) as a positron emission tomography (PET) probe for imaging the activity of N-acylethanolamine hydrolyzing enzymes in the brain. Following intravenous administration of 18F-FHEA in Swiss Webster mice, 18F-FHEA was extracted from blood by the brain and underwent hydrolysis at the amide bond and incorporation of the resultant 18F-fluorofatty acid into complex lipid pools. Pretreatment of mice with the FAAH inhibitor URB-597 (1 mg/kg IP) resulted in significantly slower 18F-FHEA incorporation into lipid pools, but overall 18F 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 18F-FHEA in the brain. Although evidence was found that 18F-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. (Chemical Equation Presented).
AB - N-Acylethanolamines are lipid signaling molecules found throughout the plant and animal kingdoms. The best-known mammalian compound of this class is anandamide, Narachidonoylethanolamine, 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-(16-18F-fluorohexadecanoyl)- ethanolamine (18F-FHEA) as a positron emission tomography (PET) probe for imaging the activity of N-acylethanolamine hydrolyzing enzymes in the brain. Following intravenous administration of 18F-FHEA in Swiss Webster mice, 18F-FHEA was extracted from blood by the brain and underwent hydrolysis at the amide bond and incorporation of the resultant 18F-fluorofatty acid into complex lipid pools. Pretreatment of mice with the FAAH inhibitor URB-597 (1 mg/kg IP) resulted in significantly slower 18F-FHEA incorporation into lipid pools, but overall 18F 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 18F-FHEA in the brain. Although evidence was found that 18F-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. (Chemical Equation Presented).
KW - F-FHEA
KW - Endocannabinoids
KW - N-(16-F-fluorohexadecanoyl)ethanolamine
KW - N-acylethanolamines
KW - PET
UR - http://www.scopus.com/inward/record.url?scp=84923256184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84923256184&partnerID=8YFLogxK
U2 - 10.1021/cn400214j
DO - 10.1021/cn400214j
M3 - Article
C2 - 25003845
AN - SCOPUS:84923256184
VL - 5
SP - 793
EP - 802
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 9
ER -