Development of a Highly Specific 18F-Labeled Radioligand for Imaging of the Sigma-2 Receptor in Brain Tumors

  • J Med Chem. 2023 Sep 13. doi: 10.1021/acs.jmedchem.3c00735.
Tao Wang  1  2 ,  Jingqi Wang  1 ,  Leyuan Chen  3 ,  Xiaojun Zhang  4 ,  Tiantian Mou  5 ,  Xiaodan An  1 ,  Jinming Zhang  4 ,  Xiaoli Zhang  5 ,  Winnie Deuther-Conrad  6 ,  Yiyun Huang  7 ,  Hongmei Jia  1
Affiliations
  • 1. Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
  • 2. Department of Nuclear Medicine, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.
  • 3. Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, Tianjin 300192, China.
  • 4. Department of Nuclear Medicine, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
  • 5. Department of Nuclear Medicine, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
  • 6. Institute of Radiopharmaceutical Cancer Research, Department of Neuroradiopharmaceuticals, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 04318 Leipzig, Germany.
  • 7. Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, Connecticut 06520-8048, United States.
PMID: 37704582 DOI: 10.1021/acs.jmedchem.3c00735
Abstract

Novel ligands with the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline or 5,6-dimethoxyisoindoline pharmacophore were designed and synthesized for evaluation of their structure-activity relationship to the sigma-2 (σ2) receptor and developed as suitable PET radioligands. Compound 1 was found to possess nanomolar affinity (Ki(σ1) = 2.57 nM) for the σ2 receptor, high subtype selectivity (>2000-fold), and high selectivity over 40 Other receptors and transporters. Radioligand [18F]1 was prepared with radiochemical yield of 37-54%, > 99% radiochemical purity, and molar activity of 107-189 GBq/μmol. Biodistribution and blocking studies in mice and micro-PET/CT imaging of [18F]1 in rats indicated excellent binding specificity to the σ2 receptors in vivo. Micro-PET/CT imaging of [18F]1 in the U87MG glioma xenograft model demonstrated clear tumor visualization with high tumor uptake and tumor-to-background ratio. Co-injection with CM398 (5 μmol/kg) led to a remarkable reduction of tumor uptake (80%, 60-70 min), indicating high specific binding of [18F]1 in U87MG glioma xenografts.

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