Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON, M1C 1A4, Canada.
J Biol Inorg Chem. 2014 Feb;19(2):229-35. doi: 10.1007/s00775-013-1073-6. Epub 2014 Jan 10.
As the first clinically approved gadolinium-based blood-pool MRI contrast agent, gadofosveset was designed to bind to human serum albumin (HSA) reversibly, extending the circulation time in the bloodstream. This valuable pharmacokinetic property required for vasculature imaging, however, raises the risk of release and accumulation of gadolinium in vivo. The binding of gadofosveset to HSA significantly increases the relaxivity at low field, which decreases drastically when the magnetic field increases, limiting the applications of gadofosveset at fields of 3 T and higher. To address those challenges, we evaluated a novel dimeric manganese(III) porphyrin (MnP2) in vitro and in vivo as a potential gadolinium-free blood-pool agent. Through multiple spectroscopic studies, we demonstrated that MnP2 binds to HSA tightly. MnP2 exhibits a moderate relaxivity decrease on HSA binding. Nevertheless, owing to the unique field-dependent relaxation behaviors and the dimeric construct (two Mn(III) ions per complex), MnP2-HSA has a molar relaxivity twice that of the gadofosveset-HSA complex at 3 T. Through intravenous injection in rats, MnP2 exhibits long retention and significant contrast enhancement in the vascular compartment, as tested in a 3-T high-field clinical MRI scanner. Taken together, these data demonstrate that MnP2 represents a new class of gadolinium-free blood-pool agents suitable for both regular and high-field applications.
作为首个经临床批准的基于钆的血池 MRI 对比剂，加氟磷酸钠旨在与人血清白蛋白（HSA）可逆结合，延长血液循环时间。然而，这种用于血管成像的宝贵药代动力学特性增加了体内释放和积累钆的风险。加氟磷酸钠与 HSA 的结合显著增加了低场下的弛豫率，而当磁场增加时，弛豫率会急剧下降，限制了加氟磷酸钠在 3T 及更高场强下的应用。为了解决这些挑战，我们评估了一种新型二聚锰（III）卟啉（MnP2）作为潜在的无钆血池造影剂的体外和体内性能。通过多项光谱研究，我们证明 MnP2 与 HSA 紧密结合。MnP2 在与 HSA 结合时表现出适度的弛豫率降低。然而，由于独特的场依赖弛豫行为和二聚体结构（每个复合物中有两个 Mn(III)离子），MnP2-HSA 在 3T 时的摩尔弛豫率是加氟磷酸钠-HSA 复合物的两倍。通过在大鼠体内静脉注射，MnP2 在血管腔内表现出长时间保留和显著的对比增强，在 3T 高场临床 MRI 扫描仪中进行了测试。综上所述，这些数据表明 MnP2 代表了一类新的无钆血池造影剂，适用于常规和高场应用。
