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

项目概要/摘要 钆基造影剂（GBCA）对于诊断放射学至关重要， 所有磁共振成像（MRI）检查，代表美国超过1200万次检查 每一年。GBCA为检测和分期不同的癌症、多发性硬化症、动脉瘤提供了重要的见解 和血管阻塞。在肾功能差的患者中，单次GBCA给药可导致 肾源性系统性纤维化（NSF），一种非常痛苦和衰弱的纤维化疾病，其中钆（Gd） 在皮肤和内部器官中发现沉积物。肾功能正常的患者也容易出现Gd 保留，并可能出现NSF样症状。尽管转向化学上更稳定的大环 在脑、骨、心、肝等组织中已检测到GBCAs、Gd，但其临床意义尚不明确， 其重要性仍有待充分理解。一个关键问题是，我们缺乏测量Gd 在成像后仍然留在体内，它被保留在哪里，以及它是如何被贩运的。在临床前阶段，新 响应性GBCA，其弛豫率响应于局部刺激（如pH值变化）而变化， 强大的工具来询问病理微环境。然而，退耦弛豫率从 体内浓度变化已被证明是难以实现的，限制了这些响应性探针的应用。 我最近表明，钇-86螯合物是理想的替代品，其相应的GBCA都在体外 和体内。86 Y PET / GBCA MR是一种无创、高灵敏度的技术，可定量报告脑内的 体内Gd浓度、分布和形态，并且容易转化为人类。86 Y PET/MR支持 体内弛豫率的测量，其告知Gd形态并可用于测量生物化学性质， 通过使用响应式MR探头进行处理。例如，细胞外pH（pHe）是细胞内pH的关键标志物。 肿瘤代谢，可以告知预后和治疗反应。在本提案中，我将使用86 Y PET/MR 解决围绕现有和下一代GBCA的三个基本和未解决的问题：1） 是否有一种GBCA可以更有效地消除，从而提供安全益处？2)是什么 保留Gd的形态，即化学和生物形式，是否有毒性证据？以及3）可以 同步86 Y PET/MR能够用响应MR探针进行定量分子成像， 用pH响应MR探针测量细胞外肿瘤pH。 这项工作的产出将是一个定量PET/MR协议的发展，以遵循体内生化 非侵入性地处理。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。

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.