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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‐2269 was synthesized and evaluated in animals as a potential MR contrast agent for blood pool. The ligand of MP‐2269 was prepared by conjugating 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 yielded spin‐lattice relaxivities (R1) for MP‐2269 of 6.2, 20.0 and 26.1 mM−1 sec−1 in water, rabbit blood, and human blood, respectively. The enhanced relaxivities in blood indicate sig nificant binding of the agent to blood proteins. At a dose of 45 μmol/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 (∼70% in 24 h by this mode). The LD50 value of MP‐2269 is ∼3.0 mmol/kg in mice. Preliminary MR angiograms obtained in the rabbit showed excellent enhancement of blood vessels. Hence, MP‐2269 has potential for future exploitation as a contrast agent for MR angiography.