Development of fluorinated GluN2B-NMDA receptor ligands for positron emission tomography (PET)
Final Report Abstract
This project is devoted to develop a fluorinated PET tracer to image and analyze NMDA receptors containing the GluN2B subunit in the central nervous system. At first, synthetic methods were established to obtain various β- and γ-fluorinated primary amines with a terminal phenyl moiety (compounds 4 – 6) and 2-fluoro-4-phenylbutyraldehyde (7). These fluorinated building blocks were used to replace the benzylpiperidino moiety of potent GluN2B ligands by aliphatic fluorinated side chains. In particular in the classes of benzo[7]annulen-7-amines and 3-benzazepines some ligands with low nanomolar GluN2B affinity were detected (e.g. 12a: Ki = 17 nM; 13k: Ki= 25 nM; 14i: Ki = 16 nM). However, the selectivity over σ1 and/or σ2 receptors has to be improved for most of the compounds. In the second part, the synthesis of novel tricyclic tetrahydrooxazolo[4,5-h]-[3]benzazepin-9-ols 8 was developed. These compounds serve as bioisosteres of tetrahydro-3-benzazepin-1,7-diols. The replacement of the phenol of 3-benzazepinediols by the benzoxazolone system inhibits the fast glucuronidation of the phenol of the potent GluN2B antagonist 2. In receptor binding studies the phenylbutyl derivative 8d (Ki = 422 nM) and the ketone 8i (Ki = 88 nM) showed the highest GluN2B affinity, which translates into inhibition of ion flux through the NMDA receptor associated ion channel. In the next step, we plan the introduction of an F-atom and later 18-F into the promising benzoxazolone class of GluN2B antagonists. In the third part of the project, F-atoms were introduced into the terminal phenyl moiety of phenylbutyl substituted 3-benzazeines. The p-and ofluorophenyl substituted derivatives 9 and 11 showed promising GluN2B affinity, high selectivity over related targets, in particular σ receptors, promising kinetics and very good imaging properties. Blocking experiments with potent GluN2B ligands confirmed the specific labeling of regions in the central nervous system, which are known for their high GluN2B expression. It is planned to bring the enantiomerically pure eutomer, i.e. the (R)-configured o-fluorophenyl derivative [18F](R)-11 into the clinic. For this purpose, we are currently working on a novel radiosynthesis, which will allow the production of enantiomerically pure [18F](R)-11 under GMP conditions.
Publications
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Replacement of benzylpiperidine moiety with fluorinated phenylalkyl side chains for the development of GluN2B receptor ligands. ChemMedChem 2018, 13, 2522 - 2529
S. Thum, D. Schepmann, D. V. Kalinin, S. M. Ametamey, B. Wünsch
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Identification and preclinical evaluation of a radiofluorinated benzazepine derivative for imaging the GluN2B subunit of the ionotropic NMDA receptor. J. Nucl. Med. 2019, 60, 259 - 266
A. Haider, I. Iten, H. Ahmed, A. Müller Herde, S. Gruber, S. D. Krämer, C. Keller, R. Schibli, B. Wünsch, L. Mu, S. M. Ametamey
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Structure-affinity relationships of 2,3,4,5-Tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues and the discovery of a radiofluorinated 2,3,4,5-tetrahydro-1H-3-benzazepine congener for imaging GluN2B subunit-containing N-methyl-D-aspartate receptors. J. Med. Chem. 2019, 62, 9450 - 9470
H. Ahmed, A. Haider, J. Varisco, M. Stankovic, R. Wallimann, S. Gruber, I. Iten, A. Müller Herde, C. Keller, R. Schibli, D. Schepmann, L. Mu, B. Wünsch, S. M. Ametamey
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Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen-7- amines as GluN2B-selective NMDA receptor antagonists. J. Labelled Compd. Radiopharm. 2019, 69, 354 - 379
S. Thum, D. Schepmann, R. F. Reinoso, I. Alvarez, S. M. Ametamey, B. Wünsch
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Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity. Eur. J. Med. Chem. 2019, 177, 47 - 62
S. Thum, D. Schepmann, E. Ayet, M. Pujol, F. R. Nieto, S. M. Ametamey, B. Wünsch
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Preclinical development of 18F-OF-NB1 for imaging GluN2B-containing N- methyl-D-aspartate receptors and its utility as a biomarker for amyotrophic lateral sclerosis. J. Nucl. Med. 2021, 62, 259 - 265
H. Ahmed, R. Wallimann, A. Haider, V. Hosseini, S. Gruber, M. Robledo, T. Nguyen, A. Müller Herde, I. Iten, C. Keller, V. Vogel, R. Schibli, B. Wünsch, L. Mu, S. M. Ametamey
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Negative allosteric modulators of NMDA receptors with GluN2B subunit: Alanine-derived benoxazolone bioisosters of 2-methyl-3-benzazepine-1,7-diols. Arch. Pharm. 2022, e2200177
A. Markus, B. Frehland, D. Schepmann, B. Wünsch
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Phenol–benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B-selective N-methyl-D-aspartate receptor antagonists. Arch. Pharm. 2022, e2200147
A. Markus, J. A. Schreiber, G. Goerges, B. Frehland, G. Seebohm, D. Schepmann, B. Wünsch
