Novel <sup>18</sup>F‑Labeled Benzimidazolone-Based\nRadioligands as Highly Selective Sigma‑2 Receptor Probes for\nTumor Imaging

Novel sigma-2 (σ<sub>2</sub>) receptor ligands with benzimidazolone\nand 5,6-dimethoxyisoindoline as pharmacophores were designed and synthesized.\nCompound <b>4</b> exhibited low nanomolar affinity for the σ<sub>2</sub> receptors (<i>K</i><sub>i</sub>(σ<sub>2</sub>) = 2.30 nM) and high subtype selectivity (<i>K</i><sub>i</sub>(σ<sub>1</sub>)/<i>K</i><sub>i</sub>(σ<sub>2</sub>) > 1500). Radioligand [<sup>18</sup>F]<b>4</b> was\nprepared in radiochemical yields of 18 ± 7%, with >99% radiochemical\npurity and molar activity of 244 ± 136 GBq/μmol. Biodistribution\nand blocking studies in mice and small animal PET/CT imaging in rats\nindicated highly specific binding of [<sup>18</sup>F]<b>4</b> in organs known to express the σ<sub>2</sub> receptors. Small\nanimal PET/CT imaging with [<sup>18</sup>F]<b>4</b> showed clear\nvisualization of the tumors in subcutaneous A549 lung cancer and U87MG\nglioma xenografts, and intracranial orthotopic U87MG glioma models.\nCo-administration of CM398 with [<sup>18</sup>F]<b>4</b> significantly\nreduced activity uptake in the tumors, indicating that [<sup>18</sup>F]<b>4</b> specifically binds to the σ<sub>2</sub> receptors\nexpressed in A549 and U87MG xenografts.