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 monoga dolinated MRI blood-pool agent. METHODS. The molecular modeling of P792 was described The r(1) relaxivity p roperties of P792 were measured in water and 4% human serum albumin at diff erent magnetic fields (20, 40, 60 MHz). The stability of the gadolinium com plex was assessed. The pharmacokinetic and biodistribution profiles were st udied in rabbits. Renal tolerance in dehydrated rats undergoing selective i ntrarenal injection was evaluated. Hemodynamic safety in rats and in vitro histamine and leukotriene B-4 release were also tested. RESULTS. The mean diameter of P792 is 50.5 Angstrom and the r(1) relaxivity of this monogadolinium contrast agent is 29 L . mmol(-1) . . s(-1) at 60 M Hz. The stability of the gadolinium complex in transmetallation is excellen t. The pharmacokinetic and biodistribution profiles are consistent with tha t of a rapid-clearance blood-pool agent: P792 is mainly excreted by glomeru lar filtration, and its diffusion across normal endothelium is limited. Ren al and hemodynamic safety is comparable to that of the nonspecific agent ga dolinium-tetraazacyclododecane tetraacetic acid. No histamine or leukotrien e B-4 release was found in RBL-2H3 isolated mastocytes. CONCLUSIONS. The relaxivity of P792 at clinical field is very high for a mo nogadolinium complex without protein binding. The pharmacokinetic and biodi stribution profiles are consistent with those of a rapid-clearance blood-po ol agent. Its initial safety profile is satisfactory. Experimental and clin ical studies are underway to confirm the potential of P792 in MRI.