Improving the Effectiveness of ParaCEST Agents by Controlling the Conformation

通过控制构象提高 ParaCEST 药物的有效性

• 批准号: 7874779
• 负责人: MARK WOODS
• 金额: $ 19.65万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7874779
• 关键词: Address; Adopted; Amides; Area; Brain Diseases; Charge; Chemicals; Clinical; Clinical Medicine; Contrast Media; Data; Detection; Development; Diagnosis; Diagnostic; Dose; Effectiveness; Employee Strikes; Environment; Generations; Goals; Grant; Histocompatibility Testing; Human; Image; Injury; Ischemia; Kinetics; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Measurable; Metabolic; Metabolism; Methods; Molecular Conformation; Molecular Weight; Morphologic artifacts; Motion; Movement; Patients; Physiologic pulse; Positioning Attribute; Reporting; Research; Role; Scanning; Scientist; Signal Transduction; Solutions; Stroke; Techniques; Technology; Tissues; Toxic effect; Variant; Vertebral column; Water; Work; arm; base; carboxylate; clinical Diagnosis; improved; in vivo; information gathering; interest; nanoparticle; particle; public health relevance; radiologist; ratiometric; research study; theories; tool; tumor

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.

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（靶向剂）的存在，或者通过信号增加对当前重要的内源性感兴趣物种（响应剂）的存在做出反应。目前可用的造影剂对于增强 MRI 的诊断能力来说是非常成功且有价值的工具；然而，它们的作用方式完全是非特定的。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代理，并且这种代理可以大幅增加 MR 成像收集的信息的数量和价值。例如，如果可以诱导试剂定位于癌症等患病组织类型中，那么很明显肿瘤诊断会变得多么容易。如果它们能够对内源性物质（例如 H+ 或乳酸）的变化做出反应，那么显然，缺血（例如中风时发生的缺血）的诊断就会变得更加容易。 Gd3+ 螯合物（传统的 MR 试剂）和超顺磁性纳米颗粒（例如 SPIO）都被广泛认为是“智能”试剂，并取得了一些惊人的成果。尽管如此，尽管取得了这些进步，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/成像后设置，其中从对比后图像中减去对比前图像，在图像采集之间或过程中患者的任何移动都会严重破坏成像结果的有效性。如果反应剂的浓度已知，则反应剂只能提供有关存在的内源物质水平的信息。 ParaCEST 试剂是一类新型显像剂，可为这些问题提供潜在的解决方案。 paraCEST 代理生成的对比度可由操作员打开或关闭。应用低能量预饱和脉冲来开启对比度；如果不施加脉冲，则会获取“无对比度”图像。因此，通过使用 paraCEST 代理，可以通过交错采集同时获取对比前和对比后图像。通过这种方式，可以减少甚至消除运动伪影。同样，通过引入比例检测方法，可以使响应剂的使用更加可行。比例法比较同一药剂的两种不同效果，是一种与浓度无关的信息获取方法。 ParaCEST 试剂已被证明适合比例检测，这表明响应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：其检测限比传统 Gd3+ 螯合物高约一个数量级。当考虑到人类的 Gd3+ 典型剂量为 5 - 10g 时，这一缺陷的严重程度就更加明显。除非能够降低 paraCEST 试剂的检测限，否则它们提供的潜在好处将永远无法在实际成像环境中实现。该资助提出了一些方法，通过这些方法可以控制和改进 paraCEST 剂的水交换动力学，以获得更大的 CEST 和更低的检测限。水交换率是控制 paraCEST 剂产生的 CEST 量的关键因素。为了控制水交换动力学，我们打算应用之前成功控制 Gd3+ 中水交换速率的方法。根据理论和初步数据，我们相信这些方法将把 paraCEST 试剂的检测限降低到至少传统 Gd3+ 螯合物的检测限，甚至可能更高。如果这些目标能够实现，将为开发可实际应用于成像实验的新靶向和响应试剂打开大门。 公众健康相关性：新一代“智能”MRI 造影剂的开发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 药物仍然比其他药物具有一些潜在优势。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，否则无法实现这些潜在的优点。这笔赠款旨在研究降低这些检测极限的方法，从而为 MR 成像开辟全新的前景。