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Title

Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers

Authors
Dubost, Emmanuelle
Dumas, Noé
Fossey, Christine
Magnelli, Rosa
Butt-Gueulle, Sabrina
Ballandonne, Céline
Caignard, Daniel H
Dulin, Fabienne
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Published in Journal of Medicinal Chemistry. 2012, vol. 55, no. 22, p. 9693-9707
Abstract The work described herein aims at finding new potential ligands for the brain imaging of 5-HT(4) receptors (5-HT(4)Rs) using single-photon emission computed tomography (SPECT). Starting from the nonsubstituted phenanthridine compound 4a, exhibiting a K(i) value of 51 nM on the 5-HT(4)R, we explored the structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to an increase of both the affinity and selectivity for 5-HT(4)R, suggesting the design of the antagonist 4v, exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT(4)R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[(123)I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate {[(123)I]1, [(123)I]SB 207710} both in vitro and in vivo in brain. Compound 11d was radiolabeled with [(125)I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT(4)R.
Keywords AnimalsDioxanes/pharmacologyDrug DesignHumansIodine RadioisotopesLigandsMiceMolecular ProbesPiperidines/pharmacologyRadioligand AssayRadiopharmaceuticalsReceptors, Serotonin, 5-HT4/chemistry/metabolismSerotonin 5-HT4 Receptor Antagonists/chemical synthesis/pharmacologyStructure-Activity RelationshipTomography, Emission-Computed, Single-Photon
Identifiers
PMID: 23102207
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Research group Neuroimagerie moléculaire en psychiatrie (983)
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DUBOST, Emmanuelle et al. Synthesis and structure-affinity relationships of selective high-affinity 5-HT(4) receptor antagonists: application to the design of new potential single photon emission computed tomography tracers. In: Journal of Medicinal Chemistry, 2012, vol. 55, n° 22, p. 9693-9707. https://archive-ouverte.unige.ch/unige:92657

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Deposited on : 2017-03-16

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