Frequency Shifting Paramagnetic Agents: Quantitative MRI of Exchange Effects

描述(申请人提供)：分子成像是一个快速发展的领域，它结合了传统的成像方法，如PET/CT、NIR、US或MRI，以及对特定生化事件做出反应的目标生物传感器。磁共振成像为分子成像应用提供了许多吸引人的特征：它在任何深度提供出色的解剖分辨率，不涉及电离辐射，并且对形态和化学重排具有内在的敏感性。后者在MRI上表现为典型的影像对比。提高对比敏感度的常见方法之一是使用造影剂，如Gd3+的外源络合物、氧化铁颗粒或内源性代谢基团。核磁共振分子成像的各种应用目前正在开发中，如细胞跟踪和受体成像、基因表达、酶活性和pH。为了充分发挥分子磁共振成像的潜力，拥有“智能”和高灵敏度的磁共振成像对比度是至关重要的。最近，一些顺磁性稀土络合物被引入到化学交换饱和转移(CEST)磁共振成像中。这些试剂的潜在优势之一是能够通过应用射频辐射来打开和关闭对比度。如果射频处于“关闭”状态，该试剂不会干扰常规的磁共振成像序列。如果射频处于“开”状态，则会在试剂浓度区域产生对比度。在常规的PARACEST实验中，在稀土离子交换质子的频率位置施加一个射频饱和脉冲。当这种方法应用于Tm3+和Dy3+等快速交换和快速松弛的稀土元素时，可能需要超过FDA指南的能量沉积，从而使许多新的发展不适用于体内。最近，引入了一种检测这些试剂的替代方法，其中将RF制备序列应用于自由水共振：关于共振顺磁化学交换效应(OPARACHEE)。以Waltz-16*为制备序列，成功地在体内外检测了一种TM3+试剂。OPARACHEE的优势包括低得多的射频功率沉积，以及不需要事先知道与镧系元素结合的质子共振的准确频率。原则上，顺磁性络合物对试剂的环境非常敏感。特别是，靶向药物正在开发中，这些药物在葡萄糖、乳糖、羟基磷脂或白蛋白等代谢物存在的情况下改变其化学交换性质。因此，重要的是不仅能够检测试剂的存在，而且能够提供关于体内试剂的交换特征和浓度的定量信息。今天，没有足够的范例将实验中测量的OPARACHEE效应大小与汇率和集中度联系起来。我们建议开发这样一个范式，从基本理论模型一直到成功的体内定量检测。

DESCRIPTION (provided by applicant): Molecular Imaging is a rapidly evolving field combining conventional imaging methodologies such as PET/CT, NIR, US or MRI with targeted biosensors responsive to a particular biochemical event. MRI offers a number of attractive features for molecular imaging applications: it provides excellent anatomical resolution at any depth, involves no ionizing irradiation, and is intrinsically sensitive to morphological and chemical rearrangements. The latter is typically manifested in MRI as image contrast. One of the common ways to improve contrast sensitivity is to use contrast agents, such as exogenous complexes of Gd3+, iron oxide particles or endogenous metabolic groups. Various applications of MRI molecular imaging are currently under development, such as cell tracking and imaging of receptors, gene expression, enzyme activity and pH. To achieve the full potential of molecular MRI it is crucial to have "smart" and highly sensitive MRI contrast. Recently, PARACEST agents were introduced in which complexes of PARAmagnetic lanthanides are used for Chemical Exchange Saturation Transfer (CEST) MRI. One of the potential advantages of these agents is the ability to turn the contrast "on" and "off" via application of RF irradiation. If the RF is "off" the agent will not interfere with conventional MR imaging sequences. If the RF is "on" contrast will be generated in areas of agent concentration. In the conventional PARACEST experiment, an RF saturation pulse is applied on the frequency position of the lanthanide-bound exchanging protons. This approach, when applied to fast exchanging and fast relaxing lanthanides like Tm3+ and Dy3+, may require power deposition exceeding FDA guidelines and thus render many new developments inapplicable in-vivo. Recently, an alternative methodology was introduced for the detection of these agents, in which an RF preparation train is applied on the free water resonance: On resonance PARamagnetic CHemical Exchange Effects (OPARACHEE). Using WALTZ-16* as the preparation train a Tm3+ agent was successfully detected invitro and in-vivo. The advantages of OPARACHEE include much lower RF power deposition and elimination of the need to know a priori the exact frequency of the lanthanide-bound proton resonances. In principle, the paramagnetic complexes can be very sensitive to the environment of the agent. In particular, targeted agents are under development, which change their chemical exchange properties in the presence of metabolites, such as glucose, lactose, hydroxyapetite or albumin. Hence, it is important to be able to not only detect the presence of the agent, but also to provide quantitative information about the exchange characteristics and the concentration of the agent in-vivo. Today, there is no adequate paradigm connecting OPARACHEE effect magnitudes measured in the experiment with the exchange rates and concentration. We propose to develop such a paradigm starting from the basic theoretical model all the way through to successful quantitative detection in-vivo.