2. Academic Validation
  3. Radiosynthesis and evaluation of novel 18F labeled PET ligands for imaging monoacylglycerol lipase

Radiosynthesis and evaluation of novel 18F labeled PET ligands for imaging monoacylglycerol lipase

  • Eur J Med Chem. 2025 Mar 5:285:117246. doi: 10.1016/j.ejmech.2025.117246.
Yinlong Li 1,  Wakana Mori 2,  Ahmad Chaudhary 1,  Chunyu Zhao 1,  Tomoteru Yamasaki 2,  Zachary Zhang 1,  Siyan Feng 1,  Tim Ware 3,  Jian Rong 1,  Masayuki Fujinaga 2,  Jiahui Chen 1,  Katsushi Kumata 2,  Yiding Zhang 2,  Kuan Hu 2,  Lin Xie 2,  Xin Zhou 1,  Zhendong Song 1,  Yabiao Gao 1,  Zhenkun Sun 4,  Jimmy S Patel 5,  Chuangyan Zhai 1,  Katherine Y Yuan 1,  Thomas L Collier 1,  Chongzhao Ran 6,  Ludovic Collin 7,  Achi Haider 7,  Uwe Grether 7,  Matthias B Wittwer 7,  Benjamin F Cravatt 3,  Ming-Rong Zhang 8,  Steven H Liang 9
Affiliations

Affiliations

  • 1 Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA, 30322, United States.
  • 2 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan.
  • 3 The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, United States.
  • 4 Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, United States.
  • 5 Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA, 30322, United States; Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, 30322, United States.
  • 6 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02114, United States.
  • 7 F. Hoffmann -La Roche Ltd, Roche. Innovation Center Basel, Switzerland by Roche Pharma Research and Early Development (pRED), Roche Innovation Center Basel, 4070, Basel, Switzerland.
  • 8 Department of Advanced Nuclear Medicine Sciences, Institute for Quantum Medical Sciences, National Institutes for Quantum Science and Technology, Chiba, 263-8555, Japan. Electronic address: zhang.ming-rong@qst.go.jp.
  • 9 Department of Radiology and Imaging Sciences, Emory University, 1364 Clifton Road, Atlanta, GA, 30322, United States. Electronic address: steven.liang@emory.edu.
PMID: 39793441 DOI: 10.1016/j.ejmech.2025.117246
Abstract

Monoacylglycerol Lipase (MAGL) is a 33 kDa cytosolic serine hydrolase that is widely distributed in the central nervous system and peripheral tissues. MAGL hydrolyzes monoacylglycerols into fatty acids and glycerol, playing a crucial role in endocannabinoid degradation. Inhibition of MAGL in the brain elevates levels of 2-arachidonoylglycerol and leads to decreased pro-inflammatory prostaglandin and thromboxane production. As such, MAGL is considered a potential target for treating neuropsychiatric disorders, metabolic syndromes, and Cancer. Based on a novel spirocyclic system, we synthesized two fluorinated carbamate scaffolds as reversible MAGL inhibitors (epimers: (R)-6, IC50 = 18.6 nM and (S)-6, IC50 = 1.6 nM). In vitro autoradiography studies of [18F](R)-6 (codenamed [18F]MAGL-2304) and [18F](S)-6 (codenamed [18F]MAGL-2305) demonstrated heterogeneous distribution and specific binding affinity to MAGL-rich brain regions. Autoradiography with MAGL knockout mouse brain tissues confirmed the binding specificity of [18F](S)-6. Dynamic PET imaging studies revealed that [18F](S)-6 exhibited limited brain uptake and homogenous distribution in rat brains. In vivo P-gp inhibition enhanced [18F](S)-6 uptake in the brain, suggesting that [18F](S)-6 constitutes a P-gp efflux substrate. This research could provide new directions in the design of MAGL PET ligands that are based on spirocyclic scaffolds.

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