PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates
Abstract
Here, the fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ~95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previousmore »
- Authors:
-
- Massachusetts General Hospital, Charlestown, MA (United States); Harvard Medical School, Boston, MA (United States)
- Harvard Medical School, Boston, MA (United States); Massachusetts General Hospital, Charlestown, MA (United States)
- Univ. of Toronto, Toronto, ON (Canada)
- Publication Date:
- Research Org.:
- Massachusetts General Hospital, Charlestown, MA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1440558
- Grant/Contract Number:
- SC0008430
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular Pharmaceutics
- Additional Journal Information:
- Journal Volume: 11; Journal Issue: 11; Journal ID: ISSN 1543-8384
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; FAAH; fatty acid amide hydrolase; kinetic modeling; PET; positron emission tomography; [18F]DOPP
Citation Formats
Rotstein, Benjamin H., Wey, Hsiao -Ying, Shoup, Timothy M., Wilson, Alan A., Liang, Steven H., Hooker, Jacob M., and Vasdev, Neil. PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates. United States: N. p., 2014.
Web. doi:10.1021/mp500316h.
Rotstein, Benjamin H., Wey, Hsiao -Ying, Shoup, Timothy M., Wilson, Alan A., Liang, Steven H., Hooker, Jacob M., & Vasdev, Neil. PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates. United States. https://doi.org/10.1021/mp500316h
Rotstein, Benjamin H., Wey, Hsiao -Ying, Shoup, Timothy M., Wilson, Alan A., Liang, Steven H., Hooker, Jacob M., and Vasdev, Neil. Tue .
"PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates". United States. https://doi.org/10.1021/mp500316h. https://www.osti.gov/servlets/purl/1440558.
@article{osti_1440558,
title = {PET Imaging of Fatty Acid Amide Hydrolase with [18F]DOPP in Nonhuman Primates},
author = {Rotstein, Benjamin H. and Wey, Hsiao -Ying and Shoup, Timothy M. and Wilson, Alan A. and Liang, Steven H. and Hooker, Jacob M. and Vasdev, Neil},
abstractNote = {Here, the fatty acid amide hydrolase (FAAH) regulates endocannabinoid signaling. [11C]CURB, an irreversibly binding FAAH inhibitor, has been developed for clinical research imaging with PET. However, no fluorine-18 labeled radiotracer for FAAH has yet advanced to human studies. [18F]DOPP ([18F]3-(4,5-dihydrooxazol-2-yl)phenyl (5-fluoropentyl)carbamate) has been identified as a promising 18F-labeled analogue based on rodent studies. The goal of this work is to evaluate [18F]DOPP in nonhuman primates to support its clinical translation. High specific activity [18F]DOPP (5–6 Ci·μmol–1) was administered intravenously (iv) to three baboons (2M/1F, 3–4 years old). The distribution and pharmacokinetics were quantified following a 2 h dynamic imaging session using a simultaneous PET/MR scanner. Pretreatment with the FAAH-selective inhibitor, URB597, was carried out at 200 or 300 μg/kg iv, 10 min prior to [18F]DOPP administration. Rapid arterial blood sampling for the first 3 min was followed by interval sampling with metabolite analysis to provide a parent radiotracer plasma input function that indicated ~95% baseline metabolism at 60 min and a reduced rate of metabolism after pretreatment with URB597. Regional distribution data were analyzed with 1-, 2-, and 3-tissue compartment models (TCMs), with and without irreversible trapping since [18F]DOPP covalently links to the active site of FAAH. Consistent with previous findings for [11C]CURB, the 2TCM with irreversible binding was found to provide the best fit for modeling the data in all regions. The composite parameter λk3 was therefore used to evaluate whole brain (WB) and regional binding of [18F]DOPP. Pretreatment studies showed inhibition of λk3 across all brain regions (WB baseline: 0.112 mL/cm3/min; 300 μg/kg URB597: 0.058 mL/cm3/min), suggesting that [18F]DOPP binding is specific for FAAH, consistent with previous rodent data.},
doi = {10.1021/mp500316h},
journal = {Molecular Pharmaceutics},
number = 11,
volume = 11,
place = {United States},
year = {Tue Jul 08 00:00:00 EDT 2014},
month = {Tue Jul 08 00:00:00 EDT 2014}
}
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