Autor(es):
Martins, Andre F. 
; Morfin, Jean-François ; Geraldes, Carlos F. G. C. ; Toth, Eva
Data: 2014
Identificador Persistente: http://hdl.handle.net/10316/25281
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): Contrast agents; Gadolinium; Magnetic resonance imaging; Lanthanides; Amyloid peptides
Descrição
In an effort towards the visualization of
b-amyloid (Ab) plaques by T1-weighted magnetic resonance
imaging for detection of Alzheimer’s disease,
we report the synthesis and characterization of stable,
noncharged Gd3? complexes of three different 1,4,7,10-
tetraazacyclododecane-1,4,7-triacetic acid monoamide
derivatives conjugated to Pittsburgh compound B, a wellestablished
marker of Ab plaques. The ligands L1, L2, and
L3 differ in the nature and size of the spacer linking the
macrocyclic chelator and the Pittsburgh compound B targeting
moiety, which affects their lipophilicity, the octanol–
water partition coefficients of the complexes ranging
from -0.15 to 0.32. Given their amphiphilic behavior, the
complexes form micelles in aqueous solution (critical
micellar concentration 1.00–1.49 mM). The parameters
determining the relaxivity, including the water exchange
rate and the rotational correlation times, were assessed for
the monomeric and the micellar form by a combined 17O
NMR and 1H nuclear magnetic relaxation dispersion
(NMRD) study. They are largely influenced by the aggregation
state and the hydrophobic character of the linkers.
The analysis of the rotational dynamics for the aggregated
state in terms of local and global motions using the Lipari–
Szabo approach indicates highly flexible, large aggregates.
On binding of the complexes to human serum albumin or to
the amyloid peptide Ab1–40 in solution, they undergo a
fourfold and a twofold relaxivity increase, respectively
(40 MHz). Proton relaxation enhancement studies confirmed
moderate interaction of Gd(L1) and Gd(L3) with
human serum albumin, with KA values ranging between
250 and 910 M-1. This work was financially supported by Fundação para a Ciência e a Tecnologia, Portugal (PhD grant SFRH/BD/
46370/2008 to AFM) and Rede Nacional de RMN (project REDE/
1517/RMN/2005) for the acquisition of the Varian VNMRS 600
NMR spectrometer in Coimbra and the French-Portuguese PESSOA
project. This work was carried out in the frame of the European
Actions TD1004 ‘‘Theragnostics Imaging and Therapy’’ and TD1007
‘‘PET-MRI’’.
