Wallace R A, Haar J P, Miller D B, Woulfe S R, Polta J A, Galen K P, Hynes M R, Adzamli K
Imaging Division, Mallinckrodt, Inc., St. Louis, Missouri 63134, USA.
Magn Reson Med. 1998 Nov;40(5):733-9. doi: 10.1002/mrm.1910400514.
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.
合成了一种名为MP - 2269的非芳香小分子钆（3 +）螯合物，并在动物体内进行了评估，作为一种潜在的血池磁共振造影剂。MP - 2269的配体是通过二天冬氨酸连接子将亲脂性的白蛋白结合部分4 - 戊基双环[2.2.2]辛烷-1 - 羧酸与氨基功能化的DTPA衍生物共轭制备而成。体外质子弛豫测量研究得出，MP - 2269在水中、兔血和人血中的自旋晶格弛豫率（R1）分别为6.2、20.0和26.1 mM⁻¹sec⁻¹。在血液中弛豫率的增强表明该造影剂与血液蛋白有显著结合。在剂量为45 μmol/kg时，MP - 2269在兔血中的清除曲线呈双相，快速和慢速成分的半衰期分别为4.7分钟和142分钟。在大鼠中，该造影剂主要通过肝胆途径清除（24小时内约70%通过此途径）。MP - 2269在小鼠中的半数致死量值约为3.0 mmol/kg。在兔身上获得的初步磁共振血管造影显示血管增强效果极佳。因此，MP - 2269有潜力在未来作为磁共振血管造影的造影剂加以利用。
