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磁共振成像在临床诊断中的作用。“智能”造影剂，报告疾病状态的特定标志物的存在(靶向试剂)，或通过增加信号对当前重要关注的内源性感兴趣物种(响应剂)的存在做出反应。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，它们的作用模式完全是非特异性的。换句话说，它们并不针对特定的组织类型，也不会对当地环境的变化做出反应。人们可以想象这样做的代理，这样的代理可以提供急剧增加的信息量和磁共振成像收集的价值。例如，如果可以诱导试剂定位于一种疾病组织类型，如癌症，那么很明显，肿瘤诊断会变得多么容易。如果它们能对H+或乳酸等内源性物种的变化做出反应，那么很明显，中风等脑缺血的诊断就会变得容易得多。Gd3+-螯合物(传统的磁共振试剂)和超顺磁性纳米粒子(如SPIO)都被广泛认为是“智能”试剂，取得了一些令人惊叹的结果。然而，尽管取得了这些进展，但在成像实验中应用这些“智能”试剂仍然存在问题。靶向试剂通常用于成像前/成像后的环境中，其中从增强后图像中减去前对比图像，患者在图像采集之间或期间的任何移动都会严重破坏成像结果的有效性。只有在已知试剂浓度的情况下，响应剂才能提供有关存在的内源物种水平的信息。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。由parCEST试剂产生的对比度可以由操作员打开或关闭。施加低能量的预饱和脉冲来开启对比度；如果没有施加该脉冲，则获得一幅没有对比度的图像。因此，通过使用parCEST试剂，可以通过交错采集来同时采集前后对比图像。这样就可以减少甚至消除运动伪影。同样，通过引入比率检测方法，可以使响应剂的使用变得更加可行。比率计量法比较同一试剂的两种不同效果，是一种不依赖于浓度的获取信息的方法。ParaCEST试剂已被证明可用于比率检测，这表明响应剂最终可能应用于活体成像工作。然而，parCEST试剂有一个主要缺点：它们的检测下限比传统的Gd3+络合物高一个数量级左右。当ON考虑到人体Gd3+的典型剂量为5-10g时，这一缺陷的规模更加明显。除非能降低parCEST试剂的检测限度，否则它们提供的潜在益处将永远无法在实际的成像环境中实现。这项授权提出了一些方法，通过这些方法可以控制和改善副CEST试剂的水交换动力学，以获得更高的CEST和更低的检测限。水交换率是控制副CEST试剂可以产生的CEST数量的关键因素。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把副CEST试剂的检测限降低到至少传统的Gd3+络合物的检测限，甚至更低。如果这些目标能够实现，将为开发新的靶向和响应性试剂打开大门，这些试剂可以实际应用于成像实验。 与公共卫生相关：新一代“智能”核磁共振造影剂的开发将对提高临床医学的诊断能力至关重要。尽管在其他领域取得了重大进展，但与替代药物相比，parCEST试剂仍然提供了一些潜在的优势。然而，除非解决这些试剂的主要缺点，即它们的高检测限，或者换句话说，高剂量要求，否则这些潜在的优势是无法实现的。这项拨款旨在研究降低这些检测极限的方法，从而为磁共振成像开辟一个全新的前景。

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.