Steroid-Based Contrast Agents for Magnetic Resonance Imaging of Endocrine Disease

描述（由申请人提供）：本研究提案的目的是开发一系列基于类固醇的磁共振成像（MRI）造影剂，以促进类固醇受体在激素依赖性疾病和发育中的状态和功能的分子表征。检测细胞受体的位置及其在整个活生物体中的浓度的能力至关重要，因为它允许进一步理解细胞信号传导机制。孕激素和雌激素是类固醇激素，它们与受体结合，在细胞核中作为转录因子发挥作用。一种非侵入性 确定乳腺依赖性肿瘤和良性病变的激素受体状态的方法可以帮助治疗选择，识别肿瘤的大小和确切位置，并在传统成像策略错过或混淆乳腺和子宫病变时提供额外的工具。与荧光和光学显微镜不同，MRI不受样本深度或透明度的限制。MRI不像正电子发射断层扫描（PET）和X射线/CT那样使用电离辐射或放射性，并且它允许随着时间的推移进行3D重建和高分辨率成像，而无需牺牲生物体。该资助提案的假设是，钆（III）结合的基于造影剂的造影剂可以靶向激素受体阳性细胞并在其中蓄积，以非侵入性成像受体状态。我们的初步研究已经确定钆（Gd）-共轭孕酮衍生物的化合物能够穿越细胞膜，结合孕酮受体，启动基因转录，并提高对比度的哺乳动物组织和肿瘤成像在体内使用磁共振，其中最有前途的是被称为“ProGlo”。该提案的重点是ProGlo的应用和扩展，以增强类固醇受体肿瘤和组织的体内成像。AIM 1.合成并测试一系列针对雌激素受体的CA。将设计和合成具有不同极性、电荷和水溶性的雌激素基造影剂，其将选择性地探测膜结合受体或位于细胞和肿瘤内的受体。AIM 2.研究乳腺和子宫激素受体疾病是否可以使用功能性激素MR药物归类为受体阳性。AIM 3.通过开发和测试生物正交、水溶性和多螯合激素CA，对CA进行化学修饰，以增强体内松弛性并降低毒性。类固醇受体由于其促进乳腺和子宫病变生长的作用而成为分子成像的有吸引力的靶点。该提案将开发类固醇造影剂，可以提供细胞中激素受体状态的分子概况，验证对治疗的反应性，并改善诊断。功能性造影剂将提供有价值的工具，用于人类，并立即用于激素受体依赖性发育和疾病的动物模型，而无需对动物实施安乐死，从而增加关于发育生物学、疾病病因学和进展的知识。

DESCRIPTION (provided by applicant): The objective of this research proposal is to develop a series of steroid-based magnetic resonance imaging (MRI) contrast agents to facilitate molecular characterization of the status and function of steroid receptors in hormone-dependent disease and development. The ability to detect the location of cell receptors and their concentration throughout a living organism is of vital importance as it allows for further understanding of cell signaling mechanics. Progesterone and estrogen are steroid hormones that bind to their receptors and function as a transcription factors in the nucleus. A non-invasive means of determining the hormone receptor status of hormone-dependent tumors and benign lesions could assist with treatment options, identification of the size and exact location of the tumor, and provide additional tools when traditional imaging strategies miss or confuse lesions of the breast and uterus. Unlike fluorescence and optical microscopy, MRI is not limited by depth or transparency of the specimen. MRI does not use ionizing radiation or radioactivity like positron emission tomography (PET) and X-ray/CT, and it allows for 3D reconstructions and high resolution imaging over time without the need to sacrifice the organism. It is the hypothesis of this grant proposal that gadolinium(III) conjugated hormone-based contrast agents can target and accumulate in hormone receptor positive cells to non-invasively image receptor status. Our preliminary studies have identified gadolinium (Gd)-conjugated progesterone derivatives as compounds capable of traversing the cell membrane, binding to progesterone receptors, initiating gene transcription, and enhancing contrast in mammalian tissues and tumors imaged in vivo using magnetic resonance, the most promising of which is termed "ProGlo". This proposal focuses on the application and expansion of ProGlo to enhance the imaging of steroid receptor tumors and tissues in vivo. AIM 1. To synthesize and test a series of CAs that targets the estrogen receptor. Estrogen-based contrast agents will be designed and synthesized with varying polarities, charges, and water solubilities that will selectively probe membrane bound receptors or receptors located inside the cells and tumors. AIM 2. To investigate if hormone receptor disease of the breast and uterus can be classified as receptor positive using functional hormone MR agents. AIM 3. To chemically modify CAs to enhance in vivo relaxivity and reduce toxicity by developing and testing bio-orthogonal, water-soluble, and multi-chelated hormone CAs. Steroid receptors have emerged as attractive targets for molecular imaging due to their role in promoting the growth of breast and uterine lesions. This proposal will develop steroid contrast agents that could provide a molecular profile of hormone receptor status in cells, validate responsiveness to therapy, and improve diagnoses. Functional contrast agents will provide valuable tools for use in humans and for immediate use in animal models of hormone receptor dependent development and disease without the need to euthanize the animal thereby increasing knowledge about developmental biology, disease etiology, and progression.