σ 2 Receptors are promising biomarkers for cancer diagnosis given the relationship between the proliferative status of tumors and their density. With the aim of contributing to the research of σ 2 receptor Positron Emission Tomography (PET) probes, we developed 2-[3-[6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl]propyl]-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal σ 2 pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling. Radiosynthesis for compound 26, which displayed the most appropriate σ 2 profile, was developed and σ 2 specific binding for the corresponding [ 18 F]-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [ 18 F]-26 could not successfully image σ 2 receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [ 18 F]-26 may still be worthy of further investigation for the imaging of σ 2 receptors in peripheral tumors devoid of P-gp overexpression.