A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA.
Chemistry. 2012 Mar 19;18(12):3675-86. doi: 10.1002/chem.201103344. Epub 2012 Feb 10.
The objective of this work was the synthesis of serum albumin targeted, Gd(III)-based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH-dependent relaxivity. Two new complexes (Gd-glu and Gd-bbu) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH-dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r(1)). In the absence of human serum albumin (HSA), r(1) increases from 2.0 to 6.0 mM(-1) s(-1) for Gd-glu and from 2.4 to 9.0 mM(-1) s(-1) for Gd-bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM) are bound (>98.9 %) to HSA (0.69 mM) over the pH range 5-8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r(1) increased 120 % (pH 5) and 550 % (pH 8.5) for Gd-glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd-bbu. The increases in r(1) at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd-bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K(d1)=0.65, K(d2)=18, K(d3)=1360 μM. The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu(III) analogue revealed that the inner-sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r(1) at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r(1) of the albumin-bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1-2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin-bound pH-dependent relaxivity.
这项工作的目的是合成血清白蛋白靶向的、具有强 pH 依赖性弛豫率的基于 Gd(III)的磁共振成像（MRI）造影剂。基于 DO3A 大环，我们合成了两种新的配合物（Gd-glu 和 Gd-bbu），该大环经修饰后，在三个环氮原子的 α 位有三个羧基烷基取代基，还有一个联苯磺酰胺臂。磺酰胺氮以 pH 依赖性方式与 Gd 配位，导致水合状态 q 降低，随着 pH 值升高而弛豫率（r(1)）降低。在没有人血清白蛋白（HSA）的情况下，Gd-glu 的 r(1)从 5 到 8.5 时从 2.0 到 6.0 mM(-1) s(-1) 增加，Gd-bbu 的 r(1)从 2.4 到 9.0 mM(-1) s(-1) 增加，这两种配合物（0.2 mM）在 37°C、0.47 T 时分别在 pH 5-8.5 范围内与 HSA（0.69 mM）结合（>98.9%）。在 pH 5-8.5 范围内，结合白蛋白可增加旋转相关时间，从而提高弛豫率。Gd-glu 的 r(1)增加了 120%（pH 5）和 550%（pH 8.5），Gd-bbu 的 r(1)增加了 42%（pH 5）和 260%（pH 8.5）。对于一个假定的缓慢翻滚 q=2 配合物，r(1)在 pH 5 时的增加出人意料地低。进一步研究了 Gd-bbu 体系。在 pH 5 时，它以逐步的方式与 HSA 结合，解离常数 K(d1)=0.65、K(d2)=18、K(d3)=1360 μM。每个结合位点的弛豫率都是恒定的。Eu(III)类似物的荧光寿命滴定实验表明，当配合物与 HSA 结合时，内球水分子被取代，导致 pH 5 时 r(1)低于预期。可变 pH 和温度核磁共振弛豫分散（NMRD）研究表明，白蛋白结合的 q=0 配合物的 r(1)增加是由于存在具有长停留时间（1-2 ns）的附近水分子。该水分子与 Gd 离子之间的距离随 pH 值变化，导致白蛋白结合的 pH 依赖性弛豫率。
