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

Tao Wang; Jingqi Wang; Leyuan Chen; Xiaojun Zhang; Tiantian Mou; Xiaodan An; Jinming Zhang; Xiaoli Zhang; Winnie Deuther-Conrad; Yiyun Huang; Hongmei Jia

doi:10.1021/acs.jmedchem.3c00735

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

J Med Chem. 2023 Sep 28;66(18):12840-12857. doi: 10.1021/acs.jmedchem.3c00735. Epub 2023 Sep 13.

Authors

Tao Wang^{1

2}, Jingqi Wang¹, Leyuan Chen³, Xiaojun Zhang⁴, Tiantian Mou⁵, Xiaodan An¹, Jinming Zhang⁴, Xiaoli Zhang⁵, Winnie Deuther-Conrad⁶, Yiyun Huang⁷, Hongmei Jia¹

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 (K_i(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.