Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies

• Published in: ChemMedChem 2018-05, Vol.13 (10), p.1058-1068
• Main Authors: Szermerski, Marina, Börgel, Frederik, Schepmann, Dirk, Haider, Ahmed, Betzel, Thomas, Ametamey, Simon M., Wünsch, Bernhard
• Format: Article
• Language: English
• Subjects: 3-benzazepines; Binding sites; Brain; Brain slice preparation; Central nervous system; Fluorination; Fluorine; Fluorine isotopes; GluN2B; Glutamic acid receptors (ionotropic); Ligands; N-Methyl-D-aspartic acid receptors; NMDA receptor; Phenols; Positron emission tomography; Radioactivity; radiosynthesis; Receptors; selectivity
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700819

To analyze the N‐methyl‐d‐aspartate (NMDA) receptor distribution in the central nervous system, fluorinated ligands that selectively address the ifenprodil binding site of GluN2B‐subunit‐containing NMDA receptors were developed. Various strategies to introduce a fluorine atom into the potent GluN2B ligand 2 (3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1,7‐diol) were pursued, including replacement of the benzylic OH moiety with a fluorine atom (13) and introduction of fluoroethoxy moieties at various positions (14 (7‐position), 17 (9‐position), 18a–c (1‐position)). With respect to GluN2B affinity and selectivity over related receptors, the fluoroethoxy derivatives 14 and 18a are the most promising ligands. Radiosynthesis of fluoroethoxy derivative [18F]14 was performed by nucleophilic substitution of the phenol 2 with 2‐[18F]fluoroethyl tosylate. On rat brain slices the fluorinated PET tracer [18F]14 accumulated in regions with high density of NMDA receptors containing GluN2B subunits. The bound radioactivity could not be replaced by (S)‐glutamate. However, the GluN2B ligands eliprodil, Ro 25‐6981, and the non‐labeled 3‐benzazepine 14 were able to abolish the specific binding of [18F]14. Tetrahydro‐3‐benzazepin‐1,7‐diols with high affinity and selectivity served as lead compounds for the development of fluorinated PET tracers for labeling of GluN2B‐subunit‐containing NMDA receptors. The 7‐(2‐fluoroethoxy) derivative shown has moderate GluN2B affinity (Ki=162 nm) yet high selectivity over related receptors. The 18F‐labeled analogue (radiochemical purity >98.9 %) was used for autoradiography of brain slices. Removal of the radioligand from its specific binding sites by various competitors (e.g., Ro 25‐6981) confirmed the selective labeling of GluN2B receptors.