The Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, 149 Thirteenth Street, Suite 2301, Charlestown, Massachusetts 02129, United States.
J Am Chem Soc. 2012 Dec 5;134(48):19858-68. doi: 10.1021/ja309187m. Epub 2012 Nov 16.
MR imaging at high magnetic fields benefits from an increased signal-to-noise ratio; however T(1)-based MR contrast agents show decreasing relaxivity (r(1)) at higher fields. High field, high relaxivity contrast agents can be designed by carefully controlling the rotational dynamics of the molecule. To this end, we investigated applications of the alanine analogue of Gd(DOTA), Gd(DOTAla). Fmoc-protected DOTAla suitable for solid phase peptide synthesis was synthesized and integrated into polypeptide structures. Gd(III) coordination results in very rigid attachment of the metal chelate to the peptide backbone through both the amino acid side chain and coordination of the amide carbonyl. Linear and cyclic monomers (GdL1, GdC1), dimers (Gd(2)L2, Gd(2)C2), and trimers (Gd(3)L3, Gd(3)C3) were prepared and relaxivities were determined at different field strengths ranging from 0.47 to 11.7 T. Amide carbonyl coordination was indirectly confirmed by determination of the hydration number q for the EuL1 integrated into a peptide backbone, q = 0.96 ± 0.09. The water residency time of GdL1 at 37 °C was optimal for relaxivity, τ(M) = 17 ± 2 ns. Increased molecular size leads to increased per Gd relaxivity (from r(1) = 7.5 for GdL1 to 12.9 mM(-1) s(-1) for Gd(3)L3 at 1.4 T, 37 °C). The cyclic, multimeric derivatives exhibited slightly higher relaxivities than the corresponding linearized multimers (Gd(2)C2: r(1) = 10.5 mM(-1) s(-1) versus Gd(2)C2-red r(1) = 9 mM(-1) s(-1) at 1.4 T, 37 °C). Overall, all six synthesized Gd complexes had higher relaxivities at low, intermediate, and high fields than the clinically used small molecule contrast agent [Gd(HP-DO3A)(H(2)O)].
磁共振成像在高磁场中受益于信噪比的提高；然而，基于 T(1)的磁共振对比剂在更高的场强下显示出弛豫率(r(1))的降低。通过仔细控制分子的旋转动力学，可以设计出高场、高弛豫率的对比剂。为此，我们研究了 Gd(DOTA)的丙氨酸类似物 Gd(DOTAla)的应用。合成了 Fmoc 保护的适合固相肽合成的 DOTAla，并将其整合到多肽结构中。Gd(III)的配位通过氨基酸侧链和酰胺羰基的配位，使金属螯合物非常牢固地连接到肽骨架上。制备了线性和环状单体（GdL1、GdC1）、二聚体（Gd(2)L2、Gd(2)C2）和三聚体（Gd(3)L3、Gd(3)C3），并在 0.47 至 11.7 T 的不同场强下测定了弛豫率。酰胺羰基的配位通过测定整合到肽骨架中的 EuL1 的水合数 q 得到间接证实，q = 0.96 ± 0.09。在 37°C 时，GdL1 的水停留时间最适合弛豫率，τ(M) = 17 ± 2 ns。分子尺寸的增加导致每 Gd 弛豫率的增加（从 GdL1 的 r(1) = 7.5 增加到 1.4 T、37°C 时 Gd(3)L3 的 12.9 mM(-1) s(-1)）。环状、多聚体衍生物的弛豫率略高于相应的线性多聚体（Gd(2)C2：r(1) = 10.5 mM(-1) s(-1)，Gd(2)C2-red r(1) = 9 mM(-1) s(-1)，在 1.4 T、37°C）。总的来说，在低、中、高场下，所有六种合成的 Gd 配合物的弛豫率都高于临床使用的小分子对比剂[Gd(HP-DO3A)(H(2)O)]。
