Rigid versus flexible anilines or anilides confirm the bicyclic ring as the hydrophobic portion for optimal σ2 receptor binding and provide novel tools for the development of future σ2 receptor PET radiotracers

Abstract

Despite their uncertain identification, σ₂ receptors are promising targets for the development of diagnostics and therapeutics for tumor diseases. Among the σ₂ ligands developed, the class of the flexible benzamides furnished an optimal pharmacophore for σ₂ receptor high affinity ligands. A recent investigation suggested that flexible benzamides bind σ₂ receptors in a bicyclic-like conformation due to an intramolecular H-bond, with 3,4-dihydroisoquinolinone derivatives reaching excellent σ₂ affinity and selectivity. Herein, the bicyclic-preferred conformation for σ₂ binding was confirmed through the development of 3,4-dihydroquinolin-(1H)2-one isomeric derivatives, 1,2,3,4-tetrahydroquinolines and the corresponding flexible anilides and anilines, all linked to the 6,7-dimethoxytetrahydroisoquinoline as a basic moiety. 3,4-Dihydroisoquinolin-(1H)2-one (10a) and 1,2,3,4-tetrahydroisoquinoline (11b) emerged for high σ₂ affinity combined to an excellent σ₂ versus σ₁ selectivity. In particular, compound 11b with its low nanomolar σ₂ affinity and impressive 2807-fold σ₂ versus σ₁ selectivity largely exceeded the biological profile of the best 3,4-dihydroisoquinolin-(2H)1-one reference compounds (1). Because of the absence of a cytotoxic effect, the modest interaction with the P-gp, an appropriate lipophilicity and the presence of easily radiolabeling functions, 11b deserves further investigation for the imaging of σ₂ receptors via PET in tumors.