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First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

A Correction to this article was published on 11 April 2022

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Abstract

Purpose

Monoacylglycerol lipase (MAGL) regulates cannabinoid neurotransmission and the pro-inflammatory arachidonic acid pathway by degrading endocannabinoids. MAGL inhibitors may accordingly act as cannabinoid-potentiating and anti-inflammatory agents. Although MAGL dysfunction has been implicated in neuropsychiatric disorders, it has never been visualized in vivo in human brain. The primary objective of the current study was to visualize MAGL in the human brain using the novel PET ligand 18F-T-401.

Methods

Seven healthy males underwent 120-min dynamic 18F-T-401-PET scans with arterial blood sampling. Six subjects also underwent a second PET scan with 18F-T-401 within 2 weeks of the first scan. For quantification of MAGL in the human brain, kinetic analyses using one- and two-tissue compartment models (1TCM and 2TCM, respectively), along with multilinear analysis (MA1) and Logan graphical analysis, were performed. Time-stability and test–retest reproducibility of 18F-T-401-PET were also evaluated.

Results

18F-T-401 showed rapid uptake and gradual washout from the brain. Logan graphical analysis showed linearity in all subjects, indicating reversible radioligand kinetics. Using a metabolite-corrected arterial input function, MA1 estimated regional total distribution volume (VT) values by best identifiability. VT values were highest in the cerebral cortex, moderate in the thalamus and putamen, and lowest in white matter and the brainstem, which was in agreement with regional MAGL expression in the human brain. Time-stability analysis showed that MA1 estimated VT values with a minimal bias even using truncated 60-min scan data. Test–retest reliability was also excellent with the use of MA1.

Conclusions

Here, we provide the first demonstration of in vivo visualization of MAGL in the human brain. 18F-T-401 showed excellent test–retest reliability, reversible kinetics, and stable estimation of VT values consistent with known regional MAGL expressions. PET with 18F-T-401-PET is promising tool for measurement of central MAGL.

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Acknowledgements

We thank Yasushi Hattori for providing animal PET data, Katsuyuki Tanimoto, Takamasa Maeda, and the members of the Translational Team for their support with PET and MRI scans, Shizuko Kawakami, Kazuko Suzuki, and Haruka Yamamoto for their assistance as clinical coordinators, the staff of the Department of Radiopharmaceuticals Development for their radioligand synthesis and metabolite analysis, Masami Nishizuka for support with arterial blood sampling, and Izumi Kaneko, Chieko Kurihara, and Atsuo Waki for monitoring and auditing of the study

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Authors and Affiliations

  1. Department of Functional Brain Imaging, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba, Chiba, 263-8555, Japan

    Keisuke Takahata, Chie Seki, Yasuyuki Kimura, Manabu Kubota, Masanori Ichise, Yasunori Sano, Yasuharu Yamamoto, Kenji Tagai, Hitoshi Shimada, Soichiro Kitamura, Kiwamu Matsuoka, Hironobu Endo, Hitoshi Shinotoh, Yuhei Takado & Makoto Higuchi

  2. Department of Neuro-Psychiatry, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo, Japan

    Keisuke Takahata

  3. Department of Clinical and Experimental Neuroimaging, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, 7-430 Morioka, Obu, Aichi, Japan

    Yasuyuki Kimura & Masanori Ichise

  4. Department of Psychiatry, Graduate School of Medicine, Kyoto University, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto, Japan

    Manabu Kubota

  5. Department of Functional Neurology & Neurosurgery, Center for Integrated Human Brain Science, Brain Research Institute, Niigata University, 1-757 Asahimachi-Dori, Chuo, Niigata, Niigata, Japan

    Hitoshi Shimada

  6. Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Science, Quantum Life and Medical Science Directorate, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage, Chiba, Chiba, Japan

    Kazunori Kawamura & Ming-Rong Zhang

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  1. Keisuke Takahata
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Contributions

Keisuke Takahata and Makoto Higuchi contributed to conception and design, acquiring, analyzing and interpreting data, drafting, and revising the manuscript. Keisuke Takahata, Chie Seki, Manabu Kubota, Yasunori Sano, Yasuharu Yamamoto, Kenji Tagai, Hitoshi Shimada, Soichiro Kitamura, Kiwamu Matsuoka, Hironobu Endo, Hitoshi Shinotoh and Yuhei Takado participated in data acquisition. Kazunori Kawamura and Ming-Rong Zhang were in charge of radioligand synthesis. Yasuyuki Kimura and Masanori Ichise contributed to analyzing and interpreting data. The first draft of the manuscript was written by Keisuke Takahata and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Keisuke Takahata.

Ethics declarations

Ethics approval and consent to participate

This study was approved by the Radiation Drug Safety Committee, and the Institutional Review Board of National Institutes for Quantum Science and Technology, Chiba, Japan, and was carried out in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. After complete description of the study, written informed consent was obtained from all participants.

Consent for publication

Written informed consent was obtained from all participants regarding publishing their data.

Competing interests

MH has received grant support from Takeda Pharmaceutical Company Limited. All other authors declare that they have no conflicts of interest. The precursor and reference standard of 18F-T-401 for the present study were provided by Takeda Pharmaceutical Company Limited. This study was supported in part by a Grant-in-Aid for Scientific Research C (20K07935), a grant from the General Insurance Association of Japan (2020–2021) to KT, a Grants-in-Aid for Brain Mapping by Integrated Neurotechnologies for Disease Studies (Brain/MINDS; 21dm0207072h0003), Strategic International Brain Science Research Promotion Program (Brain/MINDS Beyond; 20dm0307105h0002), JST Grant Number JPMJMS2024, and AMED Grant Number 20356533 to MH.

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This article is part of the Topical Collection on Neurology – Dementia

The original online version of this article was revised: The authors regret that the title that appears in the original article is incorrect.

Methods of the assessment of radiometabolites in plasma by high-performance liquid chromatography (HPLC) in the supplementary should also be corrected.

The author wrote “An aliquot of the supernatant was analyzed by radio-HPLC (Analytical column: Waters XBridge OST C18 (10 x 50 mm; particle size, 2.5 μm), acetonitrile (90 %; A) and ammonium acetate (0.02 M; B) were used as mobile phases (40/60 A/B) at a flow rate of 5.0 mL/min.”. This was incorrect. The correct description is “An aliquot of the supernatant was analyzed by radio-HPLC with a C18 column (Main column: Waters Atlantis T3 OBD Prep, 10 x 150 mm; particle size, 5 μm; guard column: Waters Atlantis T3, 10 x 10 mm; particle size, 5 μm), and the mixture of acetonitrile (A) and water (B) were used as mobile phases (A/B, 40/60) at a flow rate of 4.5 mL/min.”

The original article has been corrected.

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Takahata, K., Seki, C., Kimura, Y. et al. First-in-human in vivo imaging and quantification of monoacylglycerol lipase in the brain: a PET study with 18F-T-401. Eur J Nucl Med Mol Imaging 49, 3150–3161 (2022). https://doi.org/10.1007/s00259-021-05671-y

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