Synthesis and preliminary evaluation of MP-2269: A novel, nonaromatic small-molecule blood-pool MR contrast agent
✍ Scribed by Rebecca A. Wallace; Joe P. Haar Jr.; Donald B. Miller; Steven R. Woulfe; John A. Polta; Karen P. Galen; Michael R. Hynes; Kofi Adzamli
- Publisher
- John Wiley and Sons
- Year
- 1998
- Tongue
- English
- Weight
- 724 KB
- Volume
- 40
- Category
- Article
- ISSN
- 0740-3194
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✦ Synopsis
Abstract
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 (R~1~) 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 LD~50~ 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.