Acta Pharmaceutica Sinica B (Jun 2021)
Development of a highly-specific 18F-labeled irreversible positron emission tomography tracer for monoacylglycerol lipase mapping
- Zhen Chen,
- Wakana Mori,
- Jian Rong,
- Michael A. Schafroth,
- Tuo Shao,
- Richard S. Van,
- Daisuke Ogasawara,
- Tomoteru Yamasaki,
- Atsuto Hiraishi,
- Akiko Hatori,
- Jiahui Chen,
- Yiding Zhang,
- Kuan Hu,
- Masayuki Fujinaga,
- Jiyun Sun,
- Qingzhen Yu,
- Thomas L. Collier,
- Yihan Shao,
- Benjamin F. Cravatt,
- Lee Josephson,
- Ming-Rong Zhang,
- Steven H. Liang
Affiliations
- Zhen Chen
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Wakana Mori
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Jian Rong
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Michael A. Schafroth
- The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Tuo Shao
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Richard S. Van
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
- Daisuke Ogasawara
- The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Tomoteru Yamasaki
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Atsuto Hiraishi
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Akiko Hatori
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Jiahui Chen
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Yiding Zhang
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Kuan Hu
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Masayuki Fujinaga
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
- Jiyun Sun
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Qingzhen Yu
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Thomas L. Collier
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Yihan Shao
- Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA
- Benjamin F. Cravatt
- The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA 92037, USA
- Lee Josephson
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA
- Ming-Rong Zhang
- Department of Advanced Nuclear Medicine Sciences, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan; Corresponding authors. Tel.: +81 433 823 709, fax: +81 43 206 3261 (Ming-Rong Zhang); Tel.: +1 617 726 6107, fax: +1 617 726 6165 (Steven H. Liang).
- Steven H. Liang
- Division of Nuclear Medicine and Molecular Imaging, Massachusetts General Hospital & Department of Radiology, Harvard Medical School, Boston, MA 02114, USA; Corresponding authors. Tel.: +81 433 823 709, fax: +81 43 206 3261 (Ming-Rong Zhang); Tel.: +1 617 726 6107, fax: +1 617 726 6165 (Steven H. Liang).
- Journal volume & issue
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Vol. 11,
no. 6
pp. 1686 – 1695
Abstract
As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile SNAr reaction to form 2-[18F]fluoropyridine scaffold. Good blood–brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [18F]14 (also named as [18F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers.
