Wiener Erik C, Abadjian Marie-Caline, Sengar Raghvendra, Vander Elst Luce, Van Niekerk Christoffel, Grotjahn Douglas B, Leung Po Yee, Schulte Christie, Moore Curtis E, Rheingold Arnold L
Hillman Cancer Center, University of Pittsburgh Medical Center , 5117 Centre Avenue, Pittsburgh, Pennsylvania 15213, United States.
Inorg Chem. 2014 Jul 7;53(13):6554-68. doi: 10.1021/ic500085g. Epub 2014 Jun 16.
Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α(1)R,α(4)R,α(7)R,α(10)R)-α(1),α(4),α(7),α(10)-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, (17)O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin-avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.
磁共振成像（MRI）中外源性染料或造影剂的重要要求包括在待成像目标处有有效浓度的顺磁性或超顺磁性离子。我们报告了几种新型对映体纯的（α(1)R,α(4)R,α(7)R,α(10)R）-α(1),α(4),α(7),α(10)-四甲基-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTMA）双功能衍生物的简洁合成与表征（以及它们的1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）类似物作为对照），这些衍生物可以使用点击化学或肽偶联化学共价连接到造影剂递送系统。这些衍生物的钆配合物可以连接到递送系统，同时保持最佳的水停留时间以提高分子成像灵敏度。与抗生物素蛋白相关的铕（III）和钆（III）螯合物的长链生物素（LC-生物素）衍生物用于证明更高的效率。对配合物和生物素-抗生物素蛋白加合物使用可变温度弛豫测量、（17）O NMR和核磁共振色散（NMRD）光谱来测量水停留时间和旋转相关时间对受限和非受限系统的影响。钆（III）-DOTMA衍生物的水停留时间比钆（III）-DOTA衍生物短。与受限的钆（III）-DOTA衍生物相比，旋转受限的钆（III）-DOTMA衍生物在37°C时的弛豫率高约40%，这可以提高其作为MRI剂的灵敏度并降低靶向剂的剂量。
