title: Gadolinium-based contrast agents targeted to amyloid aggregates for the early diagnosis of Alzheimer's disease by MRI.
abstract: While important efforts were made in the development of positron emission tomography (PET) tracers for the in vivo molecular diagnosis of Alzheimer's disease, very few investigations to develop magnetic resonance imaging (MRI) probes were performed. Here, a new generation of Gd(III)-based contrast agents (CAs) is proposed to detect the amyloid β-protein (Aβ) aggregates by MRI, one of the earliest biological hallmarks of the pathology. A building block strategy was used to synthesize a library of 16 CAs to investigate structure-activity relationships (SARs) on physicochemical properties and binding affinity for the Aβ aggregates. Three types of blocks were used to modulate the CA structures: (i) the Gd(III) chelates (Gd(III)-DOTA and Gd(III)-PCTA), (ii) the biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) the linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and a difficulty of these probes to cross the blood-brain barrier (BBB). General insights for the development of Gd(III)-based CAs to detect the Aβ aggregates are described.
authors.affiliation: Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France. Electronic address: guillaume.bort@u-psud.fr.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bort
authors.affiliation: Guerbet, Centre de Recherche, BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Catoen
authors.affiliation: Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Borderies
authors.affiliation: Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France.
authors.forename: Adel
authors.initials: A
authors.lastname: Kebsi
authors.affiliation: Guerbet, Centre de Recherche, BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Ballet
authors.affiliation: Guerbet, Centre de Recherche, BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Louin
authors.affiliation: Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France; Guerbet, Centre de Recherche, BP 57400, 95943 Roissy CdG Cedex, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Port
authors.affiliation: Conservatoire national des arts et métiers, ERL 3193 Cnrs, 2 rue Conté, 75003 Paris, France.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Ferroud
mesh_terms: D000544:Alzheimer Disease / Q000000981:diagnostic imaging*; D000818:Animals; D003287:Contrast Media / Q000008:administration & dosage*; D042241:Early Diagnosis; D005682:Gadolinium / Q000008:administration & dosage*; D006801:Humans; D051379:Mice; D058225:Plaque, Amyloid / Q000000981:diagnostic imaging / Q000473:pathology*; D011877:Radionuclide Imaging
chemical_list: D003287:Contrast Media; D005682:Gadolinium
keywords: Alzheimer's disease; Amyloid; DOTA; Gadolinium; Magnetic resonance imaging (MRI); Pyridine containing TriAza (PCTA)