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 radiotracer

Despite their uncertain identification, s2 receptors are promising targets for the development of diagnostics and therapeutics for tumor diseases. Among the s2 ligands developed, the class of the flexible benzamides furnished an optimal pharmacophore for s2 receptor high affinity ligands. A recent investigation suggested that flexible benzamides bind s2 receptors in a bicyclic-like conformation due to an intramolecular H-bond, with 3,4-dihydroisoquinolinone derivatives reaching excellent s2 affinity and selectivity. Herein, the bicyclic-preferred conformation for s2 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 s2 affinity combined to an excellent s2 versus s1 selectivity. In particular, compound 11b with its low nanomolar s2 affinity and impressive 2807-fold s2 versus s1 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 s2 receptors via PET in tumors