Caravan Peter, Parigi Giacomo, Chasse Jaclyn M, Cloutier Normand J, Ellison Jeffrey J, Lauffer Randall B, Luchinat Claudio, McDermid Sarah A, Spiller Marga, McMurry Thomas J
EPIX Pharmaceuticals, Cambridge, MA 02142, USA.
Inorg Chem. 2007 Aug 6;46(16):6632-9. doi: 10.1021/ic700686k. Epub 2007 Jul 11.
The amphiphilic gadolinium complex MS-325 ((trisodium-{(2-(R)-[(4,4-diphenylcyclohexyl) phosphonooxymethyl] diethylenetriaminepentaacetato) (aquo)gadolinium(III)}) is a contrast agent for magnetic resonance angiography (MRA). MS-325 consists of two slowly interconverting diastereoisomers, A and B (65:35 ratio), which can be isolated at pH > 8.5 (TyeklAr, Z.; Dunham, S. U.; Midelfort, K.; Scott, D. M.; Sajiki, H.; Ong, K.; Lauffer, R. B.; Caravan, P.; McMurry, T. J. Inorg. Chem. 2007, 46, 6621-6631). MS-325 binds to human serum albumin (HSA) in plasma resulting in an extended plasma half-life, retention of the agent within the blood compartment, and an increased relaxation rate of water protons in plasma. Under physiological conditions (37 degrees C, pH 7.4, phosphate buffered saline (PBS), 4.5% HSA, 0.05 mM complex), there is no statistical difference in HSA affinity or relaxivity between the two isomers (A 88.6 +/- 0.6% bound, r1 = 42.0 +/- 1.0 mM(-1) s(-1) at 20 MHz; B 90.2 +/- 0.6% bound, r1 = 38.3 +/- 1.0 mM(-1) s(-1) at 20 MHz; errors represent 1 standard deviation). At lower temperatures, isomer A has a higher relaxivity than isomer B. The water exchange rates in the absence of HSA at 298 K, kA298 = 5.9 +/- 2.8 x 10(6) s(-1), kB298 = 3.2 +/- 1.8 x 10(6) s(-1), and heats of activation, DeltaHA = 56 +/- 8 kJ/mol, DeltaHB = 59 +/- 11 kJ/mol, were determined by variable-temperature 17O NMR at 7.05 T. Proton nuclear magnetic relaxation dispersion (NMRD) profiles were recorded over the frequency range of 0.01-50 MHz at 5, 15, 25, and 35 degrees C in a 4.5% HSA in PBS solution for each isomer (0.1 mM). Differences in the relaxivity in HSA between the two isomers could be attributed to the differing water exchange rates.
两亲性钆配合物MS-325（三钠-{（2-(R)-[(4,4-二苯基环己基)膦酰氧基甲基]二亚乙基三胺五乙酸根）（水合）钆(III)}）是一种用于磁共振血管造影（MRA）的造影剂。MS-325由两种缓慢相互转化的非对映异构体A和B组成（比例为65:35），在pH > 8.5时可分离出来（泰克尔，Z.；邓纳姆，S. U.；米德尔福特，K.；斯科特，D. M.；萨吉基，H.；翁，K.；劳弗，R. B.；卡拉万，P.；麦克默里，T. J.《无机化学》2007年，46卷，6621 - 6631页）。MS-325与血浆中的人血清白蛋白（HSA）结合，导致血浆半衰期延长，造影剂保留在血液隔室中，并且血浆中水合质子的弛豫率增加。在生理条件下（37℃，pH 7.4，磷酸盐缓冲盐水（PBS），4.5% HSA，0.05 mM配合物），两种异构体之间在HSA亲和力或弛豫率方面没有统计学差异（A在20 MHz时结合率为88.6±0.6%，r1 = 42.0±1.0 mM⁻¹ s⁻¹；B在20 MHz时结合率为90.2±0.6%，r1 = 38.3±1.0 mM⁻¹ s⁻¹；误差代表1个标准差）。在较低温度下，异构体A的弛豫率高于异构体B。在298 K下，无HSA时的水交换率，kA298 = 5.9±2.8×10⁶ s⁻¹，kB298 = 3.2±1.8×10⁶ s⁻¹，以及活化热，ΔHA = 56±8 kJ/mol，ΔHB = 59±11 kJ/mol，通过在7.05 T下的变温¹⁷O NMR测定。在5、15、25和35℃下，在PBS溶液中4.5% HSA的溶液中，对每种异构体（0.1 mM）记录了0.01 - 50 MHz频率范围内的质子核磁共振弛豫分散（NMRD）谱。两种异构体在HSA中的弛豫率差异可归因于不同的水交换率。
