Serum Albumin Targeted, pH-Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, GdIII-based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH-dependent relaxivity. Two new complexes (Gd-glu and Gd-bbu) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents a to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH-dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r1). In the absence of human serum albumin (HSA), r1 increases from 2.0 to 6.0 mM-1?s-1 for Gd-glu and from 2.4 to 9.0 mM-1?s-1 for Gd-bbu from pH 5 to 8.5 at 37?degrees C, 0.47 T, respectively. These complexes (0.2 mM) are bound (>98.9?%) to HSA (0.69 mM) over the pH range 58.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r1 increased 120?% (pH 5) and 550?% (pH 8.5) for Gd-glu and 42?% (pH 5) and 260?% (pH 8.5) for Gd-bbu. The increases in r1 at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd-bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants Kd1=0.65, Kd2=18, Kd3=1360 mu M. The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the EuIII analogue revealed that the inner-sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r1 at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r1 of the albumin-bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (12 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin-bound pH-dependent relaxivity

Carbazole as Linker for Dinuclear Gadolinium-Based MRI Contrast Agents

Ligands able to complex two gadolinium ions have been synthesized and characterized in view of the ability of the complexes to increase the spin relaxation of water protons. All ligands are based on the heptadentate diethylenetriaminetetraacetic acid (DTTA) chelator and carbazole as a rigid linker. Depending on the derivatization on the nitrogen atom of the five-membered ring, the compounds form small aggregates in aqueous solution, self-assemble to form micelles or bind to human serum albumin. In all cases, this leads to a marked increase in H-1 relaxivity at nuclear Larmor frequencies between 20 and 60 MHz. Water exchange on the gadolinium ions as measured by O-17 NMR relaxation is fast enough not to limit relaxivity. H-1 nuclear magnetic relaxation dispersion profiles were also measured and analyzed using Solomon-Bloembergen-Morgan theory including Lipari-Szabo treatment to include internal motion or anisotropic rotation

Design of Gd(III)-Based Magnetic Resonance Imaging Contrast Agents: Static and Transient Zero-Field Splitting Contributions to the Electronic Relaxation and Their Impact on Relaxivity

A multiple-frequency (9.4-325 GHz) and variable-temperature (276-320 K) electron paramagnetic resonance (EPR) study on low molecular weight gadolinium(III) complexes for potential use as magnetic resonance imaging (MRI) contrast agents has been performed. Peak-to-peak linewidths Hpp and central magnetic fields have been analyzed within the Redfield approximation taking into account the static zero-field splitting (ZFS) up to the sixth order and the transient ZFS up to the second order. Longitudinal electronic relaxation is dominated by the static ZFS contribution at low magnetic fields (B 1.5 T). Whereas the static ZFS clearly depends on the nature of the chelating ligand, the transient ZFS does not. For the relatively fast rotating molecules studied water proton relaxivity is mainly limited by the fast rotation and electronic relaxation has only a marked influence at frequencies below 30 MHz. From our EPR results we can conclude that electronic relaxation will have no influence on the efficiency of Gd(III)-based MRI contrast agents designed for studies at very high magnetic fields (B > 3T)