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.

Combinatorial Chemistry Online Volume 17, Issue 1, January 2015

“…Three types of blocks were used to modulate the CA structures: (i) Gd(III) chelates, (ii) biovectors (2-arylbenzothiazole, 2-arylbenzoxazole and stilbene derivatives) and (iii) linkers (neutrals, positives and negatives with several lengths). These investigations revealed unexpected SARs and provided general insights for the development of Gd(III)-based CAs [17].…”

Intracellular Transport Studies of Picolinate Macrocyclic Copper and Lanthanide Complexes

“…We believe that the influence of the complex core structure in cellular transport is too often inadequately understood, even if it is decisive for a possible clinical utilization. For example, several macrocyclic Gd MRI CAs have been proposed that aim to detect amyloid plaques inside the living brain . However, none of these molecules is able to cross the BBB and attain their targets inside the brain.…”

Lanthanide Complexes in Molecular Magnetic Resonance Imaging and Theranostics

“…recently compared a library of 16 Gd‐based contrast agents, combining a GdDOTA or GdPCTA chelate and a biovector (2‐arylbenzothiazole, 2‐arylbenzoxazole and stilbene derivatives) via a linker. The compounds targeted Aβ‐aggregates but proved difficult to cross the BBB . Austen and co‐workers reported a series of Gd‐DOTA‐small peptide conjugates which bind to β‐amyloid, but only crossed the BBB when a cationic cell penetration sequence was added and using microparticle assisted ultrasound activation …”