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