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

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 (σ 2 ) receptor and developed as suitable PET radioligands. Compound 1 was found to possess nanomolar affinity ( K i (σ 1 ) = 2.57 nM) for the σ 2 receptor, high subtype selectivity (>2000-fold), and high selectivity over 40 other receptors and transporters. Radioligand [ 18 F] 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 [ 18 F] 1 in rats indicated excellent binding specificity to the σ 2 receptors in vivo . Micro-PET/CT imaging of [ 18 F] 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 [ 18 F] 1 in U87MG glioma xenografts.