Raghunand Natarajan, Jagadish Bhumasamudram, Trouard Theodore P, Galons Jean-Philippe, Gillies Robert J, Mash Eugene A
Department of Radiology, University of Arizona, Tucson, 85724, USA.
Magn Reson Med. 2006 Jun;55(6):1272-80. doi: 10.1002/mrm.20904.
DOTA-based complexes of gadolinium (Gd) bearing a thiol moiety on a propyl or hexyl arm were synthesized. It was hypothesized that these complexes would form reversible covalent linkages with human serum albumin (HSA), which contains a reactive thiol at cysteine-34. The binding constant of the hexyl complex to HSA was measured to be 64 mM(-1) and decreased to 17, 6.1, and 3.6 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The binding constant of the propyl complex to HSA was significantly lower (5.0 mM(-1)) and decreased to 2.0, 1.5, and 0.87 mM(-1) in the presence of 0.5, 1, and 2 mM homocysteine, respectively. The longitudinal water-proton relaxivities of the hexyl and propyl complexes at 37 degrees C and 4.7 T were 2.3 and 2.9 mM(-1) s(-1), respectively, in saline. The relaxivities of the HSA-bound forms of the hexyl and propyl complexes were calculated to be 5.3 and 4.5 mM(-1) s(-1), respectively. The in vivo pharmacokinetics of both thiol complexes were altered by a chase of homocysteine but not saline, while the washout of GdDTPA was unaffected by either chase. Such redox-sensitive reversible binding of Gd complexes to plasma albumin can be exploited for imaging tissue redox and the blood-pool by MRI.
合成了基于DOTA的钆（Gd）配合物，其在丙基或己基臂上带有硫醇部分。据推测，这些配合物会与人血清白蛋白（HSA）形成可逆的共价键，HSA在半胱氨酸-34处含有一个反应性硫醇。测得己基配合物与HSA的结合常数为64 mM⁻¹，在存在0.5 mM、1 mM和2 mM同型半胱氨酸时分别降至17 mM⁻¹、6.1 mM⁻¹和3.6 mM⁻¹。丙基配合物与HSA的结合常数显著更低（5.0 mM⁻¹），在存在0.5 mM、1 mM和2 mM同型半胱氨酸时分别降至2.0 mM⁻¹、1.5 mM⁻¹和0.87 mM⁻¹。在37℃和4.7 T下，己基和丙基配合物在盐水中的纵向水质子弛豫率分别为2.3 mM⁻¹ s⁻¹和2.9 mM⁻¹ s⁻¹。计算得出己基和丙基配合物与HSA结合形式的弛豫率分别为5.3 mM⁻¹ s⁻¹和4.5 mM⁻¹ s⁻¹。两种硫醇配合物的体内药代动力学因同型半胱氨酸的追赶而改变，但不受盐水影响，而钆喷酸葡胺的洗脱不受任何一种追赶的影响。钆配合物与血浆白蛋白的这种对氧化还原敏感的可逆结合可用于通过磁共振成像对组织氧化还原和血池进行成像。
