Novel ¹⁸F-Labeled Benzimidazolone-Based Radioligands as Highly Selective Sigma-2 Receptor Probes for Tumor Imaging

Novel sigma-2 (σ2) receptor ligands with benzimidazolone and 5,6-dimethoxyisoindoline as pharmacophores were designed and synthesized. Compound 4 exhibited low nanomolar affinity for the σ2 receptors (Ki(σ2) = 2.30 nM) and high subtype selectivity (Ki(σ1)/Ki(σ2) > 1500). Radioligand [18F]4 was prepared in radiochemical yields of 18 ± 7%, with >99% radiochemical purity and molar activity of 244 ± 136 GBq/μmol. Biodistribution and blocking studies in mice and small animal PET/CT imaging in rats indicated highly specific binding of [18F]4 in organs known to express the σ2 receptors. Small animal PET/CT imaging with [18F]4 showed clear visualization of the tumors in subcutaneous A549 lung cancer and U87MG glioma xenografts, and intracranial orthotopic U87MG glioma models. Co-administration of CM398 with [18F]4 significantly reduced activity uptake in the tumors, indicating that [18F]4 specifically binds to the σ2 receptors expressed in A549 and U87MG xenografts.