Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1 H -3-benzazepine-1,7-diol - starting point for PET tracer development.

GluN2B-NMDA receptors play a key role in several neurological and neurodegenerative disorders. In order to develop novel negative allosteric GluN2B-NMDA receptor modulators, the concept of conformational restriction was pursued, i.e. the flexible aminoethanol substructure of ifenprodil was embedded into a more rigid tetrahydro-3-benzazepine system. The resulting tetrahydro-3-benzazepine-1,7-diol (±)- 2 (WMS-1410) showed promising receptor affinity in receptor binding studies ( K i  = 84 nM) as well as pharmacological activity in two-electrode-voltage-clamp experiments ( IC 50  = 116 nM) and in cytoprotective assays ( IC 50  = 18.5 nM). The interactions of ( R )- 2 with the ifenprodil binding site of GluN2B-NMDA receptors were analyzed on the molecular level and the "foot-in-the-door" mechanism was developed. Due to promising pharmacokinetic parameters (logD 7.4  = 1.68, plasma protein binding of 76-77%, sufficient metabolic stability) F-substituted analogs were prepared and evaluated as tracers for positron emission tomography (PET). Both fluorine-18-labeled PET tracers [ 18 F] 11 and [ 18 F] 15 showed high brain uptake, specific accumulation in regions known for high GluN2B-NMDA receptor expression, but no interactions with σ 1 receptors. Radiometabolites were not observed in the brain. Both PET tracers might be suitable for application in humans.