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，将常规成像方法（如PET/CT、NIR、US或MRI）与响应特定生化事件的靶向生物传感器相结合。MRI为分子成像应用提供了许多有吸引力的功能：它在任何深度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具有固有的敏感性。后者通常在MRI中表现为图像对比度。提高对比敏感度的常用方法之一是使用造影剂，例如Gd 3+的外源性络合物、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，例如细胞跟踪和受体成像，基因表达，酶活性和pH值。为了实现分子MRI的全部潜力，具有“智能”和高灵敏度的MRI对比度至关重要。最近，引入了PARACEST试剂，其中将顺磁性镧系元素的络合物用于化学交换饱和转移（CEST）MRI。这些试剂的潜在优点之一是能够通过施加RF辐射来“打开”和“关闭”对比度。如果RF“关闭”，则药剂将不会干扰常规MR成像序列。如果RF“打开”，则造影剂浓度区域将产生造影剂。在常规的PARACEST实验中，在镧系元素结合的交换质子的频率位置上施加RF饱和脉冲。当应用于快速交换和快速弛豫镧系元素如Tm 3+和Dy 3+时，这种方法可能需要超过FDA指南的功率沉积，从而使得许多新的发展不适用于体内。最近，引入了一种替代方法用于检测这些试剂，其中RF准备列车应用于自由水共振：共振顺磁化学交换效应（OPRACHEE）。以WALTZ-16* 为制备系，成功地在体外和体内检测了Tm ~（3+）药物。OPRACHEE的优点包括低得多的RF功率沉积和消除需要事先知道镧系元素结合质子共振的确切频率。原则上，顺磁性复合物可以对试剂的环境非常敏感。特别是，靶向剂正在开发中，其在代谢物如葡萄糖、乳糖、羟基磷灰石或白蛋白的存在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性和浓度的定量信息。今天，没有足够的范例连接OPRACHEE效应的大小在实验中测量的汇率和浓度。我们建议开发这样一个范例，从基本的理论模型开始，一直到成功的定量检测体内。

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.