Development of a Highly Specific 18F-labeled Radioligand for Imaging of Sigma-2 Receptor in Brain Tumor

Series of 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 (2) receptor and development as suitable PET radioligands. Compound 1 was found to possess nanomolar affinity (6.97 nM) for the 2 receptor, high subtype selectivity (58-fold) and high selectivity over 40 other receptors and transporters. Radioligand [18F]1 was prepared with radiochemical yield of 37–54%, > 99% radiochemical purity, 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 of [18F]1 to the 2 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 mol/kg) led to remarkable reduction of tumor uptake (80%, 60–70 min), indicating high specific binding of [18F]1 in U87MG glioma xenografts.