Improving the Effectiveness of ParaCEST Agents by Controlling the Conformation

描述（由申请人提供）：拟议研究的长期目标是彻底改变MRI在临床诊断中的作用。“智能”造影剂，报告疾病状态的特定标记物（靶向剂）的存在，或通过增加信号对当前显著感兴趣的内源性物种（反应性剂）的存在作出反应。目前可用的造影剂是提高MRI诊断能力的非常成功和有价值的工具；然而，它们的作用方式完全是非特异性的。换句话说，它们不针对特定的组织类型，也不会对局部环境的变化做出反应。我们可以设想这样的代理可以做到这一点，这样的代理可以在MR成像收集的信息的数量和价值上提供戏剧性的增加。例如，如果药物可以被诱导定位于病变组织类型（如癌症），那么很明显，肿瘤诊断将变得多么容易。如果它们能对H+或乳酸盐等内源性物质的变化做出反应，那么很明显，对缺血的诊断，比如中风，就会变得容易得多。Gd3+螯合剂（传统的MR试剂）和超顺磁性纳米颗粒（如SPIOs）都被广泛设想为“智能”试剂，并取得了一些惊人的成果。然而，尽管有这些进步，在成像实验中应用这些“智能”试剂仍然存在问题。靶向药物通常用于成像前/成像后的设置，其中对比前图像从对比后图像中减去，患者在图像采集之间或期间的任何运动都会严重破坏成像结果的有效性。反应性药剂只有在药剂浓度已知的情况下才能提供内源性物种水平的信息。ParaCEST显像剂是一类新的显像剂，为这些问题提供了潜在的解决方案。操作符可以打开或关闭paraCEST代理生成的对比。低能量的预饱和脉冲用于打开对比度；如果不施加脉冲，则获得“无对比度”图像。因此，使用paraCEST代理可以通过交叉获取同时获取前后对比图像。通过这种方式，可以减少甚至消除运动伪影。同样，通过引入比率检测方法，可以使反应性药剂的使用更加可行。比率法比较同一药剂的两种不同效果，是一种与浓度无关的获取信息的方法。ParaCEST试剂已被证明适用于比率检测，这表明反应性试剂最终可以应用于体内成像工作。然而，paraCEST试剂有一个主要缺点：它们的检测限比传统的Gd3+螯合物的检测限高一个数量级。当考虑到人体典型的Gd3+剂量为5 - 10g时，这种缺陷的规模就更加明显了。除非能够降低paraCEST试剂的检测极限，否则它们提供的潜在益处将永远无法在实际成像环境中实现。这项拨款提出了可以控制和改进paraCEST试剂的水交换动力学的方法，以获得更高的CEST和更低的检测限。水交换率是决定paraCEST试剂所能产生的CEST量的关键因素。为了控制水交换动力学，我们打算应用我们以前成功使用的方法来控制Gd3+中的水交换速率。从理论和初步数据来看，我们相信这些方法将使paraCEST试剂的检测限至少降低到传统Gd3+螯合物的检测限，甚至可能更高。如果这些目标能够实现，它将为开发新的靶向和反应性药物打开大门，这些药物可以实际应用于成像实验。

DESCRIPTION (provided by applicant): The long range goal of the proposed research is to revolutionize the role of MRI in clinical diagnosis. 'Smart' contrast agents that report the presence of specific marker for diseased state (targeted agents) or that respond by an increase in signal to the presence of an endogenous species of interest (responsive agents) of currently of significant interest. Currently available contrast agents are extremely successful and valuable tools for enhancing the diagnostic ability of MRI; however, their mode of action is entirely non-specific. In other words, they do not target specific tissue types, or respond to changes in the local environment. One can envision agents that would do just that, and that such agents could offer a dramatic increase in the amount and value of information gathered by MR imaging. For instance, if agents could be induced to localize in a diseased tissue type such as a cancer then it is clear how much easier tumor diagnosis could become. If they could respond to variations in endogenous species such as H+ or lactate then clearly the diagnosis of ischemia, such as occurs in a stroke, would be made that much more facile. Both Gd3+-chelates (traditional MR agents) and super-paramagnetic nanoparticles (such as SPIOs) have been widely envisioned as 'smart' agents with some striking results. Nonetheless, despite these advances there remain problems with applying these 'smart' agents in imaging experiments. Targeted agents are usually used in a pre-/post- imaging setting in which a pre- contrast image is subtracted from a post-contrast image, any movement by the patient between or during the image acquisition can seriously undermine the validity of the imaging results. Responsive agents can only provide information on the levels of endogenous species present if the concentration of the agent is known. ParaCEST agents are a new class of imaging agent that offer potential solutions to these problems. The contrast generated by paraCEST agents can be turned on or off by the operator. A low energy pre-saturation pulse is applied to turn on contrast; if the pulse is not applied then a 'without contrast' image is acquired. Thus, by using paraCEST agents the pre- and post- contrast images could be acquired simultaneously by interleaving the acquisitions. In this way motion artifacts could be reduced or even eliminated. Similarly, the use of responsive agents could be made more viable by introducing a ratiometric method of detection. Ratiometric methods compare two different effects from the same agent and are a concentration independent method of acquiring information. ParaCEST agents have been shown to be amenable to ratiometric detection suggesting that responsive agents could eventually be applied to in vivo imaging work. However, paraCEST agents suffer one major drawback: their detection limits are about one order of magnitude higher than those of traditional Gd3+ chelates. The scale of this drawback is more apparent when on considers that a typical dose of Gd3+ for a human is 5 - 10g. Unless the detection limits of paraCEST agents can be reduced then the potential benefits they offer will never be able to be realized in practical imaging settings. This grant proposes methods by which the water exchange kinetics of paraCEST agent can be controlled and improved for greater CEST and lower detection limits. Water exchange rates are a key factor in governing the amount of CEST a paraCEST agent can generate. To control water exchange kinetics we intend to apply methods that we have successfully used previously to control the water exchange rates in Gd3+. From theory and preliminary data we are confident that these methods will reduce the detection limits of paraCEST agents to at least those of traditional Gd3+ chelates and perhaps beyond. If these goals can be achieved it would open the door for new targeted and responsive agents to be developed that can be practically applied to imaging experiments. PUBLIC HEALTH RELEVANCE: The development of a new generation of 'smart' MRI contrast agents will be vital to improving the diagnostic ability of clinical medicine. Despite significant advances in other fields, paraCEST agents continue to offer some potential advantages over the alternatives. However, these potential advantages cannot be realized unless the major drawback of these agents, their high detection limits or, in other words, high dose requirements are addressed. This grant aims to investigate ways in which these detection limits can be lowered and thereby opening a whole new vista on MR imaging.