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Research ArticleNeuropharmacology

Development of an In Vivo Method to Estimate Effective Drug Doses and Quantify Fatty Acid Amide Hydrolase in Rodent Brain using Positron Emission Tomography Tracer [11C]DFMC

Tomoteru Yamasaki, Tomoyuki Ohya, Wakana Mori, Yiding Zhang, Hidekatsu Wakizaka, Nobuki Nengaki, Masayuki Fujinaga, Tatsuya Kikuchi and Ming-Rong Zhang
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 353-360; DOI: https://doi.org/10.1124/jpet.119.263772
Tomoteru Yamasaki
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Tomoyuki Ohya
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Wakana Mori
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Yiding Zhang
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Hidekatsu Wakizaka
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Nobuki Nengaki
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Masayuki Fujinaga
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Tatsuya Kikuchi
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Ming-Rong Zhang
Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, Quantum Medical Science Directorate, National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan (T.Y., T.O., W.M., Y.Z., H.W., N.N., M.F., T.K., M.-R.Z.) and SHI Accelerator Service Co. Ltd, Tokyo, Japan (N.N.)
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Abstract

Fatty acid amide hydrolase (FAAH) is a key enzyme in the endocannabinoid system. N-(3,4-Dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide ([11C]DFMC) was developed as an irreversible-type positron emission tomography (PET) tracer for FAAH. Here, we attempted to noninvasively estimate rate constant k3 (rate of transfer to the specifically-bound compartment) as a direct index for FAAH in the rat brain. First, the two-tissue compartment model analysis including three parameters [K1−k3, two-tissue compartment model for the irreversible-type radiotracer (2TCMi)] in PET study with [11C]DFMC was conducted, which provided 0.21 ± 0.04 ml·cm−3·min−1 of the net uptake value (Ki), an indirect index for FAAH, in the FAAH-richest region (the cingulate cortex). Subsequently, to noninvasively estimate Ki value, the reference model analysis (Patlak graphical analysis reference model) was tried using a time-activity curve of the spinal cord. In that result, the noninvasive Ki value (KREF) was concisely estimated with high correlation (r > 0.95) to Ki values based on 2TCMi. Using estimated KREF value, we tried to obtain calculated-k3 based on previously defined equations. The calculated k3 was successfully estimated with high correlation (r = 0.95) to direct k3 in 2TCMi. Finally, the dose relationship study using calculated k3 demonstrated that in vivo ED50 value of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate, a major inhibitor of FAAH, was 66.4 µg/kg in rat brain. In conclusion, we proposed the calculated k3 as an alternative index corresponding to regional FAAH concentrations and suggested that PET with [11C]DFMC enables occupancy study for new pharmaceuticals targeting FAAH.

SIGNIFICANCE STATEMENT In the present study, we proposed calculated k3 as an alternative index corresponding with fatty acid amide hydrolase concentration. By using calculated k3, in vivo ED50 of [3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate was successfully estimated to be 66.4 µg/kg for rats. Thus, we demonstrated the pharmacological utility of positron emission tomography with N-(3,4-dimethylisoxazol-5-yl)piperazine-4-[4-(2-fluoro-4-[11C]methylphenyl)thiazol-2-yl]-1-carboxamide.

Footnotes

    • Received November 6, 2019.
    • Accepted March 27, 2020.
  • https://doi.org/10.1124/jpet.119.263772.

  • Declaration of conflicting interests

  • The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleNeuropharmacology

Quantitative Analysis for FAAH Using PET with [11C]DFMC

Tomoteru Yamasaki, Tomoyuki Ohya, Wakana Mori, Yiding Zhang, Hidekatsu Wakizaka, Nobuki Nengaki, Masayuki Fujinaga, Tatsuya Kikuchi and Ming-Rong Zhang
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 353-360; DOI: https://doi.org/10.1124/jpet.119.263772

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Research ArticleNeuropharmacology

Quantitative Analysis for FAAH Using PET with [11C]DFMC

Tomoteru Yamasaki, Tomoyuki Ohya, Wakana Mori, Yiding Zhang, Hidekatsu Wakizaka, Nobuki Nengaki, Masayuki Fujinaga, Tatsuya Kikuchi and Ming-Rong Zhang
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 353-360; DOI: https://doi.org/10.1124/jpet.119.263772
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