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 degrees 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 (Ka) was found to be 10(4) 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.

Pharmacokinetic andin vivo evaluation of a self-assembled gadolinium(III)-iron(II) contrast agent with high relaxivity

“…The chemical structures [GdÀ1] À and [(GdÀ1) 3 Fe] À displayed potent contrast enhancement in organs including the liver with longer duration than when GdÀDTPA is used (16). In addition, [(GdÀ1) 3 Fe] À seems to be a necrosis avid contrast agent, as proved by MRIhistomorphological correlation study [ Fig.…”

“…A two-compartment distribution model was used to calculate the pharmacokinetic parameters such as the elimination half-life (T e1/2 ), the steady-state volume of distribution (VD ss ) and the total clearance (Cl tot ). The gadolinium concentrations in blood were converted to plasma concentrations by assuming a hematocrit value of 0.53 (blood volume, 58 ml/kg; plasma volume, 31 ml/kg) (16).…”

“…The relaxivity increase can also be achieved by incorporating the gadolinium(III) complexes into slowly tumbling supramolecular assemblies, such as micelles or into liposomes (9)(10)(11)(12)(13)(14)(15). High proton relaxivities may be obtained by association of metal chelates to supramolecular polymetallic assemblies (16)(17)(18)(19). The increase of molecular weight accompanying the selfassembly results in a slowdown of the tumbling rate, and hence a higher relaxivity.…”

Metalloporphyrins and Functional Analogues as MRI Contrast Agents

“…For instance, by performing dedicated tests, Hofmann et al attributed specific accumulation of Gadophrin-2 to its binding to plasma and interstitial albumin, and to the subsequent trapping in intratumoral necrotic regions [132]. However, this conclusion could not be proven by a few recent studies: one comparing a porphyrin NACA Gadophrin-2 and a strong albuminbinding blood pool CA MP2269 [67], one analyzing a chemical analogue of a nonporphyrin NACA with strengthened protein binding capacity [133], and another studying intratumoral uptake of albumin-based macromolecular therapeutic agents in human melanoma xenografts [134]. All these studies suggest that only few albumin-binding agents may possess NACA property, whereas almost all NACAs tend to reversibly bind plasma proteins (typically albumin) to a certain extent.…”

Bis(phenylethylamide) Derivatives of Gd‐DTPA as Potential Receptor‐Specific MRI Contrast Agents

“…This property, called relaxivity, depends on different factors such as the molecular mobility of the contrast agent, the water dynamics and the noncovalent binding of the contrast agent to endogenous proteins. [3,4] In recent years, new developments in molecular imaging applications have prompted the development of a novel class of contrast agents characterized by a higher contrasting ability and improved targeting capabilities.…”