Development of 3,4-dihydroisoquinolin-1(2H)-one derivatives for the Positron Emission Tomography (PET) imaging of σ2 receptors

sigma(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 sigma(2) receptor Positron Emission Tomography (PET) probes, we developed 243-16,7-dimethoxy-3,4dihydroisoquinolin-2(1H)-yllpropy11-3,4-dihydroisoquinolin-1(2H)-one (3), with optimal sigma(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 sigma(2) profile, was developed and sigma(2) specific binding for the corresponding [18F1-26 was confirmed by in vitro autoradiography on rat brain slices. Despite the excellent in vitro properties, [189-26 could not successfully image sigma(2) receptors in the rat brain in vivo, maybe because of its interaction with P-gp. Nevertheless, [189-26 may still be worthy of further investigation for the imaging of sigma(2) receptors in peripheral tumors devoid of P-gp overexpression. (C) 2013 Elsevier Masson SAS. All rights reserved.