High-affinity sigma-1 (σ) receptor ligands based on the σ antagonist PB212.

The σ receptor is a druggable target involved in many physiological processes and diseases. To clarify its physiology and derive therapeutic benefit, nine analogs based on the σ antagonist PB212 were synthesized replacing the 4-methylpiperidine with basic moieties of varying size and degree of conformational freedom. 3-Phenylpyrrolidine, 4-phenylpiperidine or granatane derivatives displayed the highest affinity (.

Novel derivatives of 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28) with improved fluorescent and σ receptors binding properties.

Despite the promising potentials of σ2 receptors in cancer therapy and diagnosis, there are still ambiguities related to the nature and physiological role of the σ2 protein. With the aim of providing potent and reliable tools to be used in σ2 receptor research, we developed a novel series of fluorescent σ2 ligands on the basis of our previous work, where high-affinity σ2 ligand 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (1, PB28) was used as the pharmacophore. Compared to the previous compounds, these novel ligands displayed improved fluorescence and σ2 binding properties, were σ2-specifically taken up by breast tumor cells, and were successfully employed in confocal microscopy.

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

σ₂ 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 σ₂ 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 σ₂ pharmacological properties and appropriate lipophilicity. Hence, 3 served as the lead compound for the development of a series of dihydroisoquinolinones amenable to radiolabeling.

Arylamides hybrids of two high-affinity σ2 receptor ligands as tools for the development of PET radiotracers.

1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine 1 (PB28) and 2-Methoxy-5-methyl-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]benzamide 2 (RHM-1) represent leads for tumor diagnosis, given their high affinity at σ(2) receptors. With the purpose of obtaining good candidates for σ(2) PET tracers development, hybrid structures between 1 and 2 were designed. Excellent σ(1)/σ(2) selectivities were reached when 6,7-dimethoxytetrahydroisoquinoline was linked to an o-methoxy substituted arylamide (11a, 12a, 15a), and for these benzamides an intramolecular H-bond in the active conformation at the σ sites, was hypothesized.