Fluorine-18-labeled benzamide analogues for imaging the σ₂ receptor status of solid tumors with positron emission tomography

A series of fluorine-containing benzamide analogs was synthesized and evaluated as candidate ligands for positron emission tomography (PET) imaging of the sigma-2 (σ₂) receptor status of solid tumors. Four compounds having a moderate to high affinity for σ₂ receptors and a moderate to low affinity for sigma-1 (σ₁) receptors were radiolabeled with fluorine-18 via displacement of the corresponding mesylate precursor with [¹⁸F]fluoride. Biodistribution studies in female Balb/c mice bearing EMT-6 tumor allografts demonstrated that all four F-18-labeled compounds had a high tumor uptake (2.5-3.7% ID/g) and acceptable tumor/ normal tissue ratios at 1 and 2 h post-i.v. injection. An analysis of the chemistry and biodistribution data suggested that N-(4-(6,7-dimethoxy-3,4- dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[¹⁸F]-fluoroethoxy)-5- methylbenzamide ([¹⁸F]3c) and N-(4-(6,7-dimethoxy-3,4- dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[¹⁸F]-fluoroethoxy)-5-iodo-3- methoxybenzamide ([¹⁸F]3f) are acceptable compounds for imaging the σ₂ receptor status of solid tumors.