Frequency Shifting Paramagnetic Agents: Quantitative MRI of Exchange Effects

描述（由申请人提供）：分子成像是一个快速发展的领域，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有反应的靶向生物传感器。MRI为分子成像应用提供了许多有吸引力的特征：它在任何深度都提供了出色的解剖分辨率，不涉及电离辐射，并且对形态和化学重排本质上很敏感。后者在MRI上通常表现为图像对比。提高对比灵敏度的常用方法之一是使用造影剂，如外源性Gd3+复合物、氧化铁颗粒或内源性代谢基团。MRI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MRI的潜力，具有“智能”和高灵敏度的MRI对比是至关重要的。最近，介绍了PARACEST试剂，其中顺磁性镧系化合物配合物用于化学交换饱和转移（CEST） MRI。这些显影剂的潜在优势之一是能够通过射频照射“打开”和“关闭”造影剂。如果RF处于“关闭”状态，该试剂将不会干扰常规的MR成像序列。如果RF处于“开启”状态，则在药剂浓度区域会产生对比。在传统的PARACEST实验中，在镧系交换质子的频率位置上施加RF饱和脉冲。这种方法，当应用于像Tm3+和Dy3+这样的快速交换和快速弛豫镧系元素时，可能需要超过FDA指南的功率沉积，从而使许多新的发展不适用于体内。最近，介绍了一种用于检测这些试剂的替代方法，其中射频制备序列应用于自由水共振：共振顺磁化学交换效应（OPARACHEE）。以华尔兹-16*为制备菌株，成功地在体外和体内检测到Tm3+制剂。OPARACHEE的优点包括低得多的射频功率沉积和不需要先验地知道镧系质子共振的确切频率。原则上，顺磁配合物对介质的环境非常敏感。特别是，靶向药物正在开发中，它们在代谢产物（如葡萄糖、乳糖、羟基磷灰石或白蛋白）存在的情况下改变其化学交换特性。因此，重要的是不仅能够检测药物的存在，而且能够提供有关药物在体内的交换特性和浓度的定量信息。目前，还没有足够的范例将实验中测量的OPARACHEE效应大小与汇率和浓度联系起来。我们建议发展这样一种范式，从基本的理论模型开始，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.