Quantification of whole-body distribution and speciation of gadolinium-based contrast agents by Y-86 PET/MRI

通过 Y-86 PET/MRI 对钆基造影剂的全身分布和形态进行量化

基本信息

批准号：
10477440
负责人：
Mariane Le Fur
金额：
$ 9.29万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477440
关键词：
Address Aneurysm Autopsy Bicarbonates Biochemical Process Biological Biology Blood Vessels Brain Chelating Agents Chemical Structure Chemicals Chromatography Contrast Media Coupled Deposition Development Diagnostic radiologic examination Doxorubicin Drug Kinetics Drug or chemical Tissue Distribution Electron Microscopy Electron Spin Resonance Spectroscopy Excision Excretory function Fibrosis Gadolinium Glucose Goals Heart Human Image Imaging Techniques In Vitro Kidney Neoplasms Magnetic Resonance Imaging Malignant Neoplasms Maps Mass Spectrum Analysis Measurement Measures Methods Microelectrodes Microscopic Modeling Monitor Multiple Sclerosis Nephrectomy Nephrogenic Systemic Fibrosis Operative Surgical Procedures Organ Output Pain Pathologic Patients Positron-Emission Tomography Predisposition Prognosis Property Protocols documentation Radiochemistry Radiolabeled Rattus Renal function Reporting Research Rodent Safety Sampling Skin Staging Stimulus Symptoms Techniques Tissue Sample Tissues Toxic effect Training Tumor Markers Work Yttrium base bone cancer imaging chemotherapy clinically significant disease diagnosis experience extracellular human tissue in vivo insight liver biopsy malignant breast neoplasm mass spectrometric imaging molecular imaging next generation pre-clinical response skills tool treatment response tumor tumor metabolism

项目摘要

Project summary/Abstract Gadolinium-based contrast agents (GBCAs) are critical for diagnostic radiology and are used in about 40% of all magnetic resonance imaging (MRI) examinations, representing over 12 million administrations in the US per year. GBCAs provide vital insight in detecting and staging different cancers, multiple sclerosis, aneurysms and vascular blockages. In patients with poor renal function a single GBCA administration can cause nephrogenic systemic fibrosis (NSF), a very painful and debilitating fibrosing condition in which gadolinium (Gd) deposits are found in the skin and internal organs. Patients with normal renal function are also prone to Gd retention and can experience NSF-like symptoms. Despite a switch to more chemically stable macrocyclic GBCAs, Gd has been detected in brain, bone, heart and liver from biopsy and autopsy tissue, but its clinical significance remains to be fully understood. A key issue is that we lack the ability to measure how much Gd remains in the body after imaging, where it is retained, and how it is trafficked. At the preclinical stage, new responsive GBCAs, whose relaxivity changes in response to a local stimulus like pH change, are emerging as powerful tools to interrogate the pathological microenvironment. However decoupling relaxivity change from concentration change in vivo has proven elusive, limiting the application of these responsive probes. I recently showed that yttrium-86 chelates are ideal surrogates for their corresponding GBCAs both in vitro and in vivo. 86Y PET / GBCA MR is a noninvasive, highly sensitive technique that quantitatively reports on the in vivo Gd concentration, distribution and speciation, and is readily translatable to humans. 86Y PET/MR enables the measurement of in vivo relaxivity which informs on Gd speciation and can be used to measure biochemical processes through the use of responsive MR probes. For example, extracellular pH (pHe) is a key marker of tumor metabolism that can inform on prognosis and treatment response. In this proposal I will use 86Y PET/MR to address three fundamental and unresolved questions surrounding existing and next generation GBCAs: 1) Is there a GBCA that is more effectively eliminated and would therefore provide a safety benefit? 2) What is the speciation, i.e. chemical and biological form(s), of the retained Gd and is there evidence of toxicity? And 3) can simultaneous 86Y PET/MR enable quantitative molecular imaging with a responsive MR probe, specifically measuring extracellular tumor pH with a pH-responsive MR probe. The output of this work will be the development of a quantitative PET/MR protocol to follow in vivo biochemical processes non-invasively. This research will provide me with vital training in PET/MR imaging, biology and pharmacokinetics, while leveraging my current skills in analytical, inorganic and radiochemistry.

项目概要/摘要钆基造影剂 (GBCA) 对于放射诊断至关重要，约 40% 的患者使用钆基造影剂所有磁共振成像 (MRI) 检查，代表美国超过 1200 万次检查每年。 GBCA 为不同癌症、多发性硬化症、动脉瘤的检测和分期提供了重要的见解和血管堵塞。对于肾功能较差的患者，单次 GBCA 给药可能导致肾源性系统性纤维化 (NSF)，一种非常痛苦且令人衰弱的纤维化病症，其中钆 (Gd) 沉积物存在于皮肤和内脏器官中。肾功能正常的患者也容易出现Gd 保留并可能出现类似 NSF 的症状。尽管改用化学更稳定的大环化合物活检和尸检组织中的脑、骨、心脏和肝脏中均检测到 GBCAs、Gd，但其临床其意义仍有待充分理解。一个关键问题是我们缺乏测量 Gd 含量的能力成像后残留在体内、保留在何处以及如何被贩运。在临床前阶段，新响应性 GBCA，其弛豫度会随着 pH 值变化等局部刺激而变化，正在成为询问病理微环境的强大工具。然而，解耦弛豫度变化体内浓度变化已被证明难以捉摸，限制了这些响应探针的应用。我最近表明，钇 86 螯合物在体外都是其相应 GBCA 的理想替代品和体内。 86Y PET / GBCA MR 是一种无创、高灵敏度技术，可定量报告内部情况体内 Gd 浓度、分布和形态，并且很容易转化为人类。 86Y PET/MR 使体内弛豫度的测量，可了解 Gd 形态并可用于测量生化通过使用响应式 MR 探头进行处理。例如，细胞外 pH (pHe) 是肿瘤代谢可以为预后和治疗反应提供信息。在这个提案中我将使用 86Y PET/MR 解决围绕现有和下一代 GBCA 的三个基本且未解决的问题： 1) 是否有一种 GBCA 可以更有效地消除并因此提供安全效益？ 2）什么是保留的 Gd 的形态，即化学和生物形式，是否有毒性证据？ 3）可以同步 86Y PET/MR 可通过响应 MR 探针进行定量分子成像，特别是使用 pH 响应 MR 探针测量细胞外肿瘤 pH 值。这项工作的成果将是开发一种定量 PET/MR 方案，以遵循体内生化非侵入式处理。这项研究将为我提供 PET/MR 成像、生物学和药代动力学，同时利用我目前在分析、无机和放射化学方面的技能。