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，其报告疾病状态的特异性标志物（靶向剂）的存在，或通过信号增加对当前显著关注的内源性感兴趣物质（响应剂）的存在作出响应。目前可用的造影剂对于增强MRI的诊断能力来说是非常成功和有价值的工具;然而，它们的作用方式完全没有特异性。换句话说，它们不针对特定的组织类型，也不对局部环境的变化做出反应。人们可以设想能够做到这一点的试剂，并且这些试剂可以提供通过MR成像收集的信息的数量和价值的显着增加。例如，如果药物可以被诱导定位在病变组织类型（如癌症）中，那么很明显肿瘤诊断会变得容易得多。如果它们能对内源性物质如H+或乳酸的变化作出反应，那么很明显，缺血的诊断，如中风，将变得更加容易。Gd 3+螯合物（传统MR试剂）和超顺磁性纳米颗粒（如SPIO）都被广泛设想为具有一些惊人结果的“智能”试剂。然而，尽管有这些进步，仍然存在问题，将这些“智能”代理在成像实验。靶向剂通常用于成像前/成像后设置中，其中从造影后图像减去造影前图像，患者在图像采集之间或期间的任何移动都可能严重破坏成像结果的有效性。如果已知试剂的浓度，则响应试剂只能提供关于存在的内源性物质的水平的信息。ParaCEST试剂是一类新的成像剂，为这些问题提供了潜在的解决方案。paraCEST试剂产生的对比度可由操作员打开或关闭。施加低能量预饱和脉冲以打开对比度;如果不施加脉冲，则采集“无对比度”图像。因此，通过使用paraCEST试剂，可以通过交错采集来同时采集造影前和造影后图像。以这种方式，可以减少或甚至消除运动伪影。同样，通过采用比率检测法，可以使敏感剂的使用更加可行。比率法比较来自同一药剂的两种不同效应，并且是获取信息的浓度无关方法。ParaCEST试剂已被证明是顺从的比率检测，这表明响应剂最终可以应用于体内成像工作。然而，paraCEST试剂具有一个主要缺点：它们的检测限比传统Gd 3+螯合物的检测限高约一个数量级。当考虑到人类的Gd 3+的典型剂量为5 - 10 g时，该缺点的规模更加明显。除非可以降低paraCEST试剂的检测限，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。该授权提出了可以控制和改进paraCEST试剂的水交换动力学以获得更大CEST和更低检测限的方法。水交换率是控制paraCEST试剂可以产生的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Gd 3+中的水交换速率。从理论和初步数据，我们相信，这些方法将降低paraCEST剂的检测限，至少传统的Gd 3+螯合物，也许超越。如果这些目标能够实现，将为开发新的靶向和响应性药物打开大门，这些药物可以实际应用于成像实验。 公共卫生相关性：开发新一代的“智能”MRI造影剂对于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，paraCEST代理商继续提供一些潜在的优势，替代品。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，否则这些潜在的优点无法实现。这项资助旨在研究降低这些检测极限的方法，从而为MR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.