Intratumoral imaging of hypoxia using 1H- and 19F-MRI with redox-responsive Eu-based contrast agents

磁共振成像（MRI）非常需要阳性造影剂， 在异质性环境中的缺氧，如在许多肿瘤中发现的缺氧， 治疗结果，开发新的治疗方法，并使我们的相关假设的测试 缺氧和人类健康之间的基本认识。我们的长期目标是发展 MRI阳性造影剂通过关注含EuII的复合物来填补诊断医学中的这一空白 这是最有前途的研究领域之一。本申请的总体目标是建立 将我们的新的基于19 F-EuII的复合物转化为有用的缺氧响应性 通过研究铕的配体上氟的位置的影响， 体外和体内缺氧指数。支持拟议研究的理由是，EuII- 含氟标记的复合物（T1或19 F）作为氧化的函数影响MRI 正如我们最近在体外和体内证明的那样，铕的状态。预期的结果是， 建议是建立具有定义的缺氧指数的基于19 F-Eu II的造影剂。这一结果 预计将产生积极的影响，有助于美国国立卫生研究院的使命在人类的理解， 疾病我们计划透过以下三个具体目标，达致建议的目的： 从我们最初的成功，我们合理设计了一系列氧化还原活性的基于Eu的多模态造影剂， （2）表征多模式的弛豫率和体外缺氧指数的温度依赖性 用于MRI的氧化还原活性的基于19 F-Eu的探针;和（3）为了定义健康小鼠中的体内缺氧指数， 小鼠和骨肉瘤的小鼠模型。新的基于19 F-EuII的探针将是重要的，因为它们是 预期能够使治疗引起的缺氧变化成像，从而有助于 评估治疗效果并影响癌症患者的护理和管理。此外，委员会认为， 由于缺氧与广泛的疾病有关，预计该提案将使收益最大化， 还有很多其他的投资。

There is a great need for positive contrast agents for magnetic resonance imaging (MRI) that respond to levels of hypoxia in heterogeneous environments like those found in many tumors for the purpose of predicting therapeutic outcomes, developing new therapies, and enabling the testing of hypotheses relevant to our collective fundamental understanding between hypoxia and human health. Our long-term goal is to develop positive contrast agents for MRI to fill this void in diagnostic medicine by focusing on EuII-containing complexes that are among the most promising areas of study. The overall objective of this application is to establish the groundwork necessary for translation of our new 19F-EuII-based complexes into useful hypoxia-responsive contrast agents by studying the influence of the position of fluorine on ligands for europium and characterizing in vitro and in vivo indices of hypoxia. The rationale that underpins the proposed research is that EuII- containing complexes labeled with fluorine differentially (T1 or 19F) influence MRI as a function of the oxidation state of europium as we have recently demonstrated both in vitro and in vivo. The expected outcome of this proposal is the establishment of 19F-EuII-based contrast agents with defined hypoxia indices. This outcome is expected to have a positive impact by contributing to the NIH's mission in the understanding of human diseases. We plan to achieve the objective of the proposal by pursuing three specific aims: (1) to synthesize a series of redox-active Eu-based multimodal contrast agents designed rationally from our initial successful agent; (2) to characterize temperature-dependence of relaxivity and in vitro hypoxia indices for multimodal redox-active 19F-Eu-based probes for MRI; and (3) To define in vivo hypoxia indices in healthy mice, hypoxic mice, and mouse models of osteosarcoma. The new 19F-EuII-based probes will be significant because they are expected to enable changes in hypoxia resulting from therapies to be imaged, consequently aiding in assessing therapeutic efficacy and influencing the care and management of cancer patients. Furthermore, because hypoxia is relevant to a wide-range of diseases, this proposal is expected to maximize returns in many other investments of the NIH.