RESUMEN
An original MRI contrast agent, called P792, is described. P792 is a gadolinium macrocyclic compound based on a Gd-DOTA structure substituted by hydrophilic arms. The chemical structure of P792 has been optimized in order to provide (1) a high r(1) relaxivity in the clinical field for MRI: 29 mM(-1)xs(-1) at 60 MHz, (2) a high biocompatibility profile and (3) a high molecular volume: the apparent hydrodynamic volume of P792 is 125 times greater than that of Gd-DOTA. As a result of this high molecular volume, P792 presents an unusual pharmacokinetic profile, as it is a Rapid Clearance Blood Pool Agent (RCBPA) characterized by limited diffusion across the normal endothelium. The original pharmacokinetic properties of this RCBPA are expected to be well suited to MR coronary angiography, angiography, perfusion imaging (stress and rest), and permeability imaging (detection of ischemia and tumor grading). Further experimental imaging studies are ongoing to define the clinical value of this compound.
Asunto(s)
Medios de Contraste/síntesis química , Medios de Contraste/farmacocinética , Gadolinio , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacocinética , Imagen por Resonancia Magnética/métodos , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/farmacocinética , Animales , Medios de Contraste/química , Compuestos Heterocíclicos/química , Indicadores y Reactivos , Dosificación Letal Mediana , Masculino , Tasa de Depuración Metabólica , Estructura Molecular , Compuestos Organometálicos/química , Ratas , Ratas Sprague-Dawley , Espectrometría de Masa por Ionización de Electrospray , Distribución TisularRESUMEN
An original gadolinium chelate, termed P760, which diffuses through the vascular endothelium but at a much lower rate than nonspecific agents (NSA), is described. P760 is a gadolinium macrocyclic compound based on a DOTA structure that is substituted by hydrophilic bulky groups branched on the amino-carboxylic residues. The molecular weight is 5293, and the molecular volume, measured by light scattering, is 30 times higher (11.5 nm3) than that of gadolinium (Gd)-DOTA (0.38 nm3). The increase in molecular volume and weight has two consequences: a) higher relaxivity (r1; 24.7 mM-1.s-1 compared with 3.4 mM-1.s-1 for Gd-DOTA at 20 Mhz, 37 degrees C); and b) a lengthening of its transport rate through the endothelium. P760 presents a peculiar pharmacokinetic profile: at early times post injection, the blood concentrations are higher than those of Gd-DOTA, but after 20 minutes, the blood concentrations are equal for the two compounds. The body clearances of the products are identical (i.e., glomerular filtration rate). P760 molecules are large enough to have a restricted diffusion through the endothelium but, conversely, small enough to pass freely through the glomerular membrane. This limited extravasation has been observed in rabbits by magnetic resonance angiography or in investigations of tumor permeability. Further experimental imaging studies are needed to define the clinical interest of such properties.
Asunto(s)
Medios de Contraste , Compuestos Organometálicos , Animales , Permeabilidad Capilar , Medios de Contraste/química , Medios de Contraste/farmacocinética , Difusión , Endotelio Vascular/metabolismo , Gadolinio , Masculino , Meglumina/química , Meglumina/farmacocinética , Ratones , Compuestos Organometálicos/química , Compuestos Organometálicos/farmacocinética , Conejos , Ratas , Ratas Wistar , Distribución TisularRESUMEN
RATIONALE AND OBJECTIVES: In this paper we discuss novel MR imaging blood pool agents characterized by new pharmacokinetic properties. METHODS: The pharmacokinetics of the products were studied in a rabbit model. The potential of these new products was demonstrated in experimental MR imaging. RESULTS AND CONCLUSION: Three main classes of blood pool agents have been defined and characterized according to their pharmacokinetic properties: low diffusion agents, rapid clearance blood pool agents, slow clearance blood pool agents. Each kind of blood pool agent is expected to have different diagnostic applications.
