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 (sigma(2)) receptor status of solid tumors. Four compounds having a moderate to high affinity for sigma(2) receptors and a moderate to low affinity for sigma-1 (sigma(1)) receptors were radiolabeled with fluorine-18 via displacement of the corresponding mesylate precursor with [F-18]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-[F-18]-fluoroethoxy)-5-methylbenzamide ([F-18]3c) and N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)butyl)-2-(2-[F-18]-fluoroethoxy)-5-iodo-3-methoxybenzamide ([F-18]3f) are acceptable compounds for imaging the sigma(2) receptor status of solid tumors.