PET IMAGING OF HYPOXIA WITH EF1 AND EF5

使用 EF1 和 EF5 进行缺氧 PET 成像

• 批准号: 6189381
• 负责人: CAMERON J KOCH
• 金额: $ 35.54万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6189381
• 关键词: bioimaging /biomedical imaging; hypoxia; imidazole; laboratory mouse; laboratory rat; neoplasm /cancer radiation therapy; nitro compounds; positron emission tomography; prognosis

Recent data has provided compelling evidence that hypoxic tumors (cervix, head and neck, soft tissue sarcoma) are resistant to the most widely used forms of therapy. In addition, hypoxic tumors are prone to metastasis. Thus, the early detection of tumor hypoxia is likely to play an important role in choosing the most appropriate therapies. A non-invasive assay for tissue hypoxia would be applicable to all tumors, many of which cannot be accessed by invasive methods, to aid in the selection the most appropriate therapy on an individual patient basis. The proposed work involves the detailed testing of two 2-nitroimidazoles, EF1 and EF5, in rodent tumor models. Such compounds are metabolically reduced forming covalent intracellular adducts at a rate which is maximal in severe hypoxia and decreases, with first order inhibition kinetics, as the oxygen concentration increases. The bound adducts can then be detected in various ways as a surrogate for the measurement of tissue hypoxia. Binding of EF5 has been thoroughly characterized using immunohistochemical techniques and has been shown to predict individual tumor response to radiation in rodents. EF5 is FDA approved for use in humans and is currently in phase I clinical trials using such methods. Results from this trial have shown no EF5-related toxicity, and anectdotal information regarding the ability of EF5 to detect prognosis-related hypoxia are encouraging. EF5, and its much more hydrophilic analog, EF1, have recently been labelled with 18F, allowing drug and adduct detection by positron emission tomography (PET). Thus, we will be able to compare invasive measurement of hypoxia, at very high resolution using immunohistochemistry, with non-invasive measurements (PET) at lower resolution. Our planned studies will allow several key aspects of non-invasive hypoxia imaging to be tested in detail: these include the effects of drug concentration, drug polarity and optimization of imaging algorithms and resolution. The last of these will greatly benefit from a new high-resolution PET camera under current development at the University of Pennsylvania. Our overall hypothesis is that assessment of hypoxia using appropriate PET imaging agents will predict radiation response in individual tumors. It should also be noted that the detection of hypoxia has wide-ranging applications in other pathologic conditions including stroke, heart attack, and wound healing.

最近的数据提供了令人信服的证据，表明缺氧肿瘤（子宫颈，头颈，软组织肉瘤）具有对最广泛使用的治疗形式的抗性。 另外，低氧肿瘤容易转移。 因此，肿瘤缺氧的早期检测可能在选择最合适的疗法中起重要作用。 对组织缺氧的非侵入性测定将适用于所有肿瘤，其中许多肿瘤无法通过侵入性方法访问，以帮助选择单个患者的最合适的治疗方法。 所提出的工作涉及对啮齿动物肿瘤模型中两个2-硝基咪唑EF1和EF5的详细测试。 此类化合物是代谢降低的，以最大的速度在严重的缺氧中最大，并且随着氧气浓度的增加而以一阶抑制动力学降低，以最大的速度减少了共价性内加合物。然后，可以以各种方式检测到结合的加合物作为测量组织缺氧的替代物。 EF5的结合已使用免疫组织化学技术彻底表征，并已被证明可以预测啮齿动物中肿瘤对辐射的单个肿瘤反应。 EF5已获得FDA批准用于人类，目前正在使用此类方法进行I期临床试验。 该试验的结果没有显示与EF5相关的毒性，并且有关EF5检测与预后相关的缺氧能力的近端信息令人鼓舞。 EF5及其亲水类似物EF1最近已标记为18F，允许通过正电子发射断层扫描（PET）进行药物和加合物检测。 因此，我们将能够使用免疫组织化学以非常高的分辨率与低分辨率（PET）进行较低分辨率的侵入性测量。 我们计划的研究将详细测试非侵入性缺氧成像的几个关键方面：其中包括药物浓度，药物极性和成像算法和分辨率的优化的影响。 在宾夕法尼亚大学目前开发的新高分辨率宠物相机中，其中的最后一个将大大受益。 我们的总体假设是，使用适当的PET成像剂评估缺氧将预测个体肿瘤的辐射反应。 还应注意的是，在其他病理状况中，缺氧的检测具有广泛的应用，包括中风，心脏病发作和伤口愈合。