Synthesis, Characterization, and Pharmacokinetic Evaluation of a Potential MRI Contrast Agent Containing Two Paramagnetic Centers with Albumin Binding Affinity

Abstract

A dinuclear gadolinium(III) complex of an amphiphilic chelating ligand, containing two diethylenetriamine‐N,N,N′,N′′,N′′‐pentaacetate (DTPA) moieties bridged by a bisindole derivative with three methoxy groups, has been synthesized and evaluated as a potential magnetic resonance imaging (MRI) contrast agent. Nuclear magnetic relaxation dispersion (NMRD) measurements indicate that at 20 MHz and 37 °C the dinuclear gadolinium(III) complex has a much higher relaxivity than [Gd(DTPA)] (6.8 vs 3.9 s⁻¹ mmol⁻¹). The higher relaxivity of the dinuclear gadolinium(III) complex can be related to its reduced motion and larger rotational correlation time relative to [Gd(DTPA)]. In the presence of human serum albumin (HSA) the relaxivity value of the noncovalently bound dinuclear complex increases to 15.2 s⁻¹ per mmol of Gd³⁺, due to its relatively strong interaction with this protein. The fitted value of the binding constant to HSA (K_a) was found to be 10⁴ M⁻¹. Because of its interaction with HSA, the dinuclear complex exhibits a longer elimination half‐life from the plasma, and a better confinement to the vascular space compared to the commercially available [Gd(DTPA)] contrast agent. Transmetalation of the dinuclear gadolinium(III) complex by zinc(II) has been investigated. Biodistribution studies suggest that the complex is excreted by the renal pathway, and possibly by the hepatobiliary route. In vivo studies indicated that half of the normal dose of the gadolinium(III) complex enhanced the contrast in hepatic tissues around 40 % more effectively than [Gd(DTPA)]. The dinuclear gadolinium(III) complex was tested as a potential necrosis avid contrast agent (NACA), but despite the binding to HSA, it did not exhibit necrosis avidity, implying that binding to albumin is not a key parameter for necrosis‐targeting properties.