SYNTHESIS AND PRELIMINARY EVALUATION OF MP-2269 - A NOVEL, NONAROMATIC SMALL-MOLECULE BLOOD-POOL MR CONTRAST AGENT

A nonaromatic, small-molecule, gadolinium(3+)-chelate code named MP-22 69 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP-2269 was prepared by conjugati ng a lipophilic, albumin-binding moiety, 4-pentylbicyclo[2.2.2]octane- 1-carboxylic acid, to an amino-functionalized DTPA derivative by means of a diaspartic acid linker. Proton relaxometry studies in vitro yiel ded spin-lattice relaxivities (R-1) for MP-2269 of 6.2, 20.0 and 26.1 mM(-1) sec(-1) in water, rabbit blood, and human brood, respectively. The enhanced relaxivities in brood indicate significant binding of the agent to blood proteins. At a dose of 45 mu mol/kg, MP-2269 showed a biphasic rabbit blood clearance profile with half-lives of 4.7 and 142 minutes, respectively, for the fast and slow components. In rats, the agent is cleared predominantly through the hepatobiliary pathway (sim ilar to 70% in 24 h by this mode). The LD50 value of MP-2269 is simila r to 3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the ra bbit showed excellent enhancement of blood vessels. Hence, MP-2269 has potential for future exploitation as a contrast agent for MR angiogra phy.