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Eur J Med Chem. 2015 Apr 13;94:386-96. doi: 10.1016/j.ejmech.2015.03.017. Epub 2015 Mar 9.

Design of a serotonin 4 receptor radiotracer with decreased lipophilicity for single photon emission computed tomography.

Author information

1
Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France.
2
Hôpitaux Universitaires de Genève, Département de Santé Mentale et de Psychiatrie, Service de Psychiatrie Générale, Unité des Biomarqueurs de Vulnérabilité, Chemin du Petit-Bel-Air, 2, CH-1225 Genève, Switzerland.
3
Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France.
4
Normandie Univ., COBRA, UMR 6014 et FR 3038, Univ. Rouen, INSA Rouen, CNRS, 1 Rue Tesnière, F-76821 Mont-Saint-Aignan Cedex, France. Electronic address: jean-philippe.bouillon@univ-rouen.fr.
5
Normandie Univ., Université de Caen Basse-Normandie, CERMN (EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE), UFR des Sciences Pharmaceutiques, Bd Becquerel, F-14032 Caen, France. Electronic address: frederic.fabis@unicaen.fr.

Abstract

With the aim to develop a suitable radiotracer for the brain imaging of the serotonin 4 receptor subtype (5-HT4R) using single photon emission computed tomography (SPECT), we synthesized and evaluated a library of di- and triazaphenanthridines with lipophilicity values which were in the range expected to favour brain penetration, and which demonstrated specific binding to the target of interest. Adding additional nitrogen atoms to previously described phenanthridine ligands exhibiting a high unspecific binding, we were able to design a radioiodinated compound [(125)I]14. This compound exhibited a binding affinity value of 0.094 nM toward human 5-HT4R and a high selectivity over other serotonin receptor subtypes (5-HTR). In vivo SPECT imaging studies and competition experiments demonstrated that the decreased lipophilicity (in comparison with our previously reported compounds 4 and 5) allowed a more specific labelling of the 5-HT4R brain-containing regions.

KEYWORDS:

5-HT; Iodine; Molecular imaging; Radiolabeling; SPECT; Serotonin

PMID:
25778994
DOI:
10.1016/j.ejmech.2015.03.017
[Indexed for MEDLINE]

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