Development of fluorinated GluN2B receptor antagonists for the positron emission tomography (PET)

Basic data for this project

Description

The NMDA (N-methyl-D-aspartate) receptor belongs to the class of ionotropic glutamate receptors. It plays an important role in cognitive processes like learning and memory but also in acute and chronic events of neuronal cell damage including stroke, injury and neurodegenerative disorders (e.g. Parkinson, Alzheimer disease). Four subunits with different expression in different regions of the central nervous system form the functional heterotetrameric NMDA receptor. This project is devoted to image GluN2B subunit containing NMDA receptors by labeling the ifenprodil binding site within the N-terminal domain of the GluN2B subunit. A fluorinated PET tracer labeling selectively GluN2B subunit containing NMDA receptors will be used for target validation and quantification of this NMDA receptor subtype under healthy and diseased conditions. In preliminary work we have developed the classes of tetrahydro-3-benzazepines and benzo[7]annulen-7-amines as GluN2B selective antagonists. Due to their high GluN2B affinity, high selectivity over other targets, promising pharmacokinetic properties including passage of the blood brain barrier, these compounds served as lead compounds for this project. In order to obtain a PET tracer a fluorine atom will be introduced at various positions of the GluN2B ligands. The GluN2B affinity, GluN2B antagonistic activity, receptor selectivity, chemical and metabolic stability, plasma protein binding, and passage of the blood brain barrier will be investigated using [19F]-labeled ligands. Optimization of the different ligand properties requires an iterative process. After selecting the most promising fluorinated GluN2B antagonists, the radiosynthesis will be performed and the [18F]-labeled PET tracers will be evaluated biologically including in vitro autoradiography, radiometabolism and biodistribution in animals. In order to confirm the specificity of the ligands blocking studies with eliprodil are planned.