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 significant binding of the agent to blood proteins. At a dose of 45 micromol/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 (approximately 70% in 24 h by this mode). The LD50 value of MP-2269 is approximately 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.
Wallace
R A
RA
Imaging Division, Mallinckrodt, Inc., St. Louis, Missouri 63134, USA.
Haar
J P
JP
Miller
D B
DB
Woulfe
S R
SR
Polta
J A
JA
Galen
K P
KP
Hynes
M R
MR
Adzamli
K
K
D000818:Animals; D003287:Contrast Media / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005069:Evaluation Studies as Topic; D019786:Gadolinium DTPA / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007928:Lethal Dose 50; D018810:Magnetic Resonance Angiography / Q000379:methods*; D051379:Mice; D011817:Rabbits; D051381:Rats; D012680:Sensitivity and Specificity; D014018:Tissue Distribution
D003287:Contrast Media; C112668:MP 2269; D019786:Gadolinium DTPA