Gadolinium(III) Di- and Tetrachelates Designed for in Vivo Noncovalent Complexation with Plasma Proteins: A Novel Molecular Design for Blood Pool MRI Contrast Enhancing Agents

Abstract

A new series of gadolinium chelates designed as blood pool contrast enhancing agents for magnetic resonance imaging applications is described. Complexes having four Gd(III) chelate units display a significant increase in molecular relaxivity per gadolinium ion in water (9-13 L x mmol(-1) x (s-1) compared to Gd(III)-DTPA (5 L x mmol(-1) x s(-1). A further jump in relaxivity (25 L x mmol(-1) x sec(-1) in 4% BSA solution was observed in the case of a fatty acid-containing tetrachelate and is attributed to noncovalent binding of the tetrachelate to serum albumin. This agent was successfully used for imaging the rat circulatory system.

Redox‐sensitive contrast agents for MRI based on reversible binding of thiols to serum albumin

“…The relative increase in relaxivity of Gd-DO3A-NH-(CH 2 ) 3 -SH upon binding to HSA (r 1,bound vs. r 1,free ) was significant, suggesting some restriction of the reorientational freedom of bound Gd. However, both the absolute and relative increases in relaxivity were low compared to increases reported for other albumin-binding complexes (25,(31)(32)(33), possibly due to the high flexibility of the acyl linker. Figure 4b depicts the relaxation enhancement produced by Gd-DO3A-NH-(CH 2 ) 6 -SH in PBS, and in PBS with 0.66 mM HSA and varying concentrations of homocysteine.…”

“…The calculated longitudinal relaxivities of HSAbound Gd-DO3A-NH-(CH 2 ) 6 -SH (r 1,bound ) were also similar at all four homocysteine concentrations ( Table 1). As with the n ϭ 3 complex, the fractional increase in relaxivity of Gd-DO3A-NH-(CH 2 ) 6 -SH upon binding to HSA (r 1,bound vs. r 1,free ) was significant, but both the relative and absolute increase in relaxivity were low compared to increases reported for other albumin-binding complexes (25,(31)(32)(33). This suggests that while there is some degree of restriction of the reorientational freedom of Gd upon binding to HSA, the increase is limited by the high flexibility of the acyl linkers.…”

A Modular System for the Synthesis of Multiplexed Magnetic Resonance Probes

“…22,36 For example, the work of Martin and coworkers is an early example of a modular agent that has been modified with a fatty acid to bind to BSA. 37 Ranganathan and coworkers have found a 25% increase in relaxivity when the number of freely rotating atoms in their linker was decreased. 38 Additionally a 40% increase in relaxivity was seen by Henig and coworkers in their silsesquioxane contrast agents by changing from an ethylene to a benzene linker.…”

Gadolinium(III) Chelates as MRI Contrast Agents: Structure, Dynamics, and Applications

“…Martin et al 252 described the preparation of some DTPA-based dimers and tetramers (Chart 21). The authors also report relaxivities in water and in 4% BSA solution and observe an increase upon measuring r 1 in the protein solution (see Table 27).…”