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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


Ahmed, Hazem; Haider, Ahmed; Varisco, Jasmine; Stanković, Maja; Wallimann, Rahel; Gruber, Stefan; Iten, Irina; Häne, Surya; Müller Herde, Adrienne; Keller, Claudia; Schibli, Roger; Schepmann, Dirk; Mu, Linjing; Wünsch, Bernhard; Ametamey, Simon M (2019). 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. Journal of Medicinal Chemistry, 62(21):9450-9470.

Abstract

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [$^{18}$F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [$^{18}$F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [$^{18}$F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

Abstract

Aspiring to develop a positron emission tomography (PET) imaging agent for the GluN2B subunits of the N-methyl-d-aspartate receptor (NMDAR), a key therapeutic target for drug development toward several neurological disorders, we synthesized a series of 2,3,4,5-tetrahydro-1H-3-benzazepine and 6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine analogues. After in vitro testing via competition binding assay and autoradiography, [$^{18}$F]PF-NB1 emerged as the best performing tracer with respect to specificity and selectivity over σ1 and σ2 receptors and was thus selected for further in vivo evaluation. Copper-mediated radiofluorination was accomplished in good radiochemical yields and high molar activities. Extensive in vivo characterization was performed in Wistar rats comprising PET imaging, biodistribution, receptor occupancy, and metabolites studies. [$^{18}$F]PF-NB1 binding was selective to GluN2B-rich forebrain regions and was specifically blocked by the GluN2B antagonist, CP-101,606, in a dose-dependent manner with no brain radiometabolites. [$^{18}$F]PF-NB1 is a promising fluorine-18 PET tracer for imaging the GluN2B subunits of the NMDAR and has utility for receptor occupancy studies.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Nuclear Medicine
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Life Sciences > Molecular Medicine
Life Sciences > Drug Discovery
Language:English
Date:14 November 2019
Deposited On:05 Feb 2020 18:49
Last Modified:29 Jul 2020 13:08
Publisher:American Chemical Society (ACS)
ISSN:0022-2623
OA Status:Closed
Publisher DOI:https://doi.org/10.1021/acs.jmedchem.9b00812
PubMed ID:31657559

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