Gd3+ complexes conjugated to Pittsburgh compound B: potential MRI markers of β-amyloid plaques

Abstract

In an effort towards the visualization of β-amyloid (Aβ) plaques by T1-weighted magnetic resonance imaging for detection of Alzheimer's disease, we report the synthesis and characterization of stable, noncharged Gd(3+) complexes of three different 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid monoamide derivatives conjugated to Pittsburgh compound B, a well-established marker of Aβ 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 (17)O NMR and (1)H 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 Aβ1-40 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).

Interaction of PiB‐Derivative Metal Complexes with Beta‐Amyloid Peptides: Selective Recognition of the Aggregated Forms

“…The micelles present at high concentration incorporate the peptide monomer by promoting the formation of two α‐helical structures separated by a flexible loop, one in the Q15–G25 region with an amphipathic surface stabilized by the micellar surface and the second in the I31–V36 region with an hydrophobic surface buried in the micelle core 10. Although our complexes do have amphiphilic behavior, with a slightly different hydrophobicity and cmc (log P =−0.15 and 0.03 and cmc=1.49 and 1.0 m M for GdL 1 and GdL 2 , respectively),24, 54 we performed all studies well below the cmc. Thus the protective effect of GdL 2 against peptide aggregation cannot be related to the stabilization of the α‐helical peptide structure by micelles.…”

Amplifying the Sensitivity of Zinc(II) Responsive MRI Contrast Agents by Altering Water Exchange Rates

“…The τ RO 298 values for these complexes calculated from the 17 O T 1 data were all in the range 0.3–0.4 ns, indicating that these complexes rotate more slowly than GdDOTA, as one would expect on the basis of molecular weight. 27,28 The inner-sphere q value of each complex was estimated from the 17 O chemical shift of the fully bound water molecule ( δ μ ). 29 All q values obtained were close to 1, except for sensor Gd- 2 , where q was found to be equal to 0.4 (Table 1).…”

Contrast agents for MRI: 30+ years and where are we going?

“…As for every in vivo application, biological barriers like the blood-brain-barrier and toxicity of the contrast agent also need to be considered. Three different approaches for targeted delivery are highlighted in this issue: Yang proposes protein-based biomarkers targeting liver tumors [49]; Sherry and Mason report a small gadolinium complex that naturally accumulates in hypoxic tumors [50]; and Tóth and coworkers use targeting moieties for imaging β-amyloid plaques [51]. …”