Physicochemical and biological evaluation of P792, a rapid-clearance blood-pool agent for magnetic resonance imaging.

RATIONALE AND OBJECTIVES To summarize the physicochemical characterization, pharmacokinetic behavior, and biological evaluation of P792, a new monogadolinated MRI blood-pool agent. METHODS The molecular modeling of P792 was described. The r1 relaxivity properties of P792 were measured in water and 4% human serum albumin at different magnetic fields (20, 40, 60 MHz). The stability of the gadolinium complex was assessed. The pharmacokinetic and biodistribution profiles were studied in rabbits. Renal tolerance in dehydrated rats undergoing selective intrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B4 release were also tested. RESULTS The mean diameter of P792 is 50.5 A and the r1 relaxivity of this monogadolinium contrast agent is 29 L x mmol(-1) x s(-1) at 60 MHz. The stability of the gadolinium complex in transmetallation is excellent. The pharmacokinetic and biodistribution profiles are consistent with that of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomerular filtration, and its diffusion across normal endothelium is limited. Renal and hemodynamic safety is comparable to that of the nonspecific agent gadolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotriene B4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS The relaxivity of P792 at clinical field is very high for a monogadolinium complex without protein binding. The pharmacokinetic and biodistribution profiles are consistent with those of a rapid-clearance blood-pool agent. Its initial safety profile is satisfactory. Experimental and clinical studies are underway to confirm the potential of P792 in MRI.

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