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

用于内分泌疾病磁共振成像的类固醇造影剂

• 批准号: 8719099
• 负责人: Thomas J Meade
• 金额: $ 33.34万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719099
• 关键词: Aging; Animal Model; Animals; Applications Grants; Benign; Binding; Biological; Biological Assay; Breast Diseases; Cell Nucleus; Cell membrane; Cells; Charge; Chemicals; Chemistry; Conjugated Estrogens; Contrast Media; Development; Developmental Biology; Diagnosis; Disease; Disease Progression; Endocrine System Diseases; Estrogen Receptors; Estrogen receptor positive; Estrogens; Etiology; Fluorescence; Gadolinium; Genetic Transcription; Growth; Hormone Receptor; Hormones; Human; Image; Imaging Techniques; Implant; In Vitro; Ionizing radiation; Knowledge; Lesion; Life; Location; Magnetic Resonance; Magnetic Resonance Imaging; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Membrane; Microscopy; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Mus; Mutagenesis; New Agents; Nuclear; Nude Mice; Oncogenic; Optics; Organism; Palpable; Pathologic Processes; Physiological Processes; Positron-Emission Tomography; Process; Progesterone; Progesterone Receptors; Property; Radioactivity; Receptor Cell; Research Proposals; Resolution; Rodent Model; Role; Safety; Series; Signal Transduction; Solubility; Specimen; Steroid Receptors; Steroids; Testing; Time; Tissues; Toxic effect; Tumor Tissue; Uterine Lesion; Uterus; Water; Women' s Health; X-Ray Computed Tomography; Xenograft procedure; base; breast lesion; cancer diagnosis; design; dimethylbenzanthracene; endometriosis; gadolinium oxide; improved; in vitro testing; in vivo; innovation; malignant breast neoplasm; molecular imaging; neoplastic cell; public health relevance; receptor; receptor binding; receptor function; recombinase; reconstruction; research study; single photon emission computed tomography; soft tissue; spatiotemporal; steroid hormone; tool; transcription factor; tumor; water solubility

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.

描述（由申请人提供）：本研究计划的目的是开发一系列基于类固醇的磁共振成像（MRI）造影剂，以促进激素依赖性疾病和发展中类固醇受体状态和功能的分子表征。检测细胞受体的位置及其在整个生物体中的浓度的能力是至关重要的，因为它允许进一步理解细胞信号传导机制。黄体酮和雌激素是类固醇激素，它们与受体结合，在细胞核中起转录因子的作用。一个非侵入性的