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Trisodium-[(2-(R)-[(4,4-diphenylcyclohexyl)phosphono-oxymethyl]-diethylenetriaminepentaacetato)(aquo)gadolinium(III) Gadofosveset.


Zhang H.


Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.
2007 Oct 24 [updated 2008 Jan 03].


The conventional x-ray angiography (XRA) provides a gold standard for diagnosis of vascular diseases (1). However, this technique requires administration of a large volume of iodinated contrast media through arterial puncture and exposes patients to a significant dose of ionizing radiation. Magnetic resonance imaging (MRI) is a non-invasive alternative to XRA that derives signals from tissue water protons without irradiation (1, 2). The difference between the signal intensity of vasculatures and that of surrounding tissues creates contrasts in MR images and results in a MR angiogram. The use of blood pool contrast agents (BPCAs) enhances the signal in vasculatures and improves the quality of MR angiograms (3). BPCAs are paramagnetic contrast agents designed to remain in the blood for a prolonged time compared to conventional contrast agents like gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) (3). BPCAs normally include macromolecules attached gadolinium chelates or iron oxide nanoparticles that are sufficiently large to prevent them from diffusing through the endothelium of normal tissue and entering the interstitial space easily. These agents can produce persistent signal-enhancing effects in a much longer acquisition time window to yield better signal-to-noise ratio and image spatial resolution. The difference between their molecular size and the pore size in the capillary endothelium of organs determines their biodistribution and elimination (3). Glomerular capillaries in the kidneys are fenestrated with pores 60–70 nm in diameter, allowing for rapid excretion of molecules <20 kDa regardless of their charges. Molecules between 20 and 70 kDa are partly or completely excreted through the kidney endothelial membrane depending on pH, lipid solubility, and polarity. Molecules >70 kDa do not pass through the glomerulus filter but are metabolized before excretion. For instance, albumin-(DTPA)30 has a plasma elimination time of 3.63 h in rats and takes ~1 month to excrete most of the gadolinium after biodegradation (3). In clinical applications, tissue retention–induced toxicity becomes a primary critical factor for the use of BPCAs. Trisodium-[(2-(R)-[(4,4-diphenylcyclohexyl)phosphono-oxymethyl] diethylenetriaminepenta-acetato)(aquo)gadolinium(III) (Gadofosveset) is a small chelate made from substituted Gd-DTPA. By binding to serum albumin in blood plasma, gadofosvesets are converted to BPCAs as macromolecules attached gadolinium chelates (4). As a well-documented 66-kDa globular protein, human serum albumin (HSA) has several specific binding sites (5). Because this protein is distributed 4.5% in blood plasma, which weighs four times more than interstitial fluid (6), HSA becomes a primary binding target for small paramagnetic chelates to generate BPCAs in situ. The specific binding site II on HSA is located in a hydrophobic cavity of 8–10 Å in diameter and has been a preferential binding site for many ligands, such as fenbufen, diazepam, and piroxicam, in drug designs (5). Gadofosveset comprises a diphenylcyclohexyl moiety attached by a phosphodiester link to Gd-DTPA to fit the specific binding site II (7). The addition of the phosphodiester group increases the hydrophilicity of the complex and the binding affinity (7). This lipophilic diphenylcyclohexyl group also enhances the thermodynamic stability and the kinetic inertness of gadofosveset compared to that of Gd-DTPA, the parent analog (8). The interaction between HSA and gadofosveset is a reversible non-covalent binding, and the equilibrium between the free and the protein-bound fraction always leaves a small amount of free fraction present (9). Such kinetics reduces the leakage of gadofosveset out of the intravascular space, but there still remains an excretion path for the free fraction filtered through the kidneys or via uptake by hepatocytes (9). The non-covalent linking overcomes the tissue retention problem found in other synthetic BPCAs like albumin-(DTPA)30. On the other hand, the bound fraction is hidden from the kidneys and leads to an extended plasma half-life. By binding to HSA via multiple groups, the T1 relaxivity of gadofosveset increases 4–10 times because of an elongation of rotation correlation time (τR) (9). This enhancement effect is substantially greater than the two- to four-fold increase in efficacy normally found in those gadolinium chelates that are covalently linked to macromolecules (3). Potential applications in clinics include enhancement of vessels in MR angiography and determination of tissue perfusion, angiogenesis, or capillary integrity (1).

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