Stable High Relaxivity MRI Contrast Agents

描述（由申请人提供）：稳定，高松弛度MRI造影剂。造影剂在临床磁共振成像（MRI）中起着重要的作用。大约三分之一的扫描使用造影剂，这些造影剂几乎都是基于钆（Gd）的T1造影剂，可以提供积极的图像对比。然而，最近，基于gd的药物与肾源性系统性纤维化（NSF）有关，NSF是一种影响肾功能不全患者的衰弱性疾病。据推测，与造影剂分离的Gd是一个致病因素。对于新的造影剂，无论是非特异性细胞外示踪剂还是靶向分子显像剂，必须解决Gd毒性的风险。解决这个问题的一种方法是设计更好的Gd配体，使其更能抵抗Gd的释放。第二种方法是增加造影剂的松弛度（r1），即T1松弛效果。高弛豫剂可以以较低剂量给予，减少病人接触金属离子。母应用程序将这两种方法协同结合，以确定新的、稳定的、高松弛的造影剂。母应用程序的目标是开发化学稳定的造影剂，在广泛的磁场范围内提供高弛豫性，并且可以很容易地“插入”到目标群体中进行分子成像。有效的、稳定的钆基配合物簇可以在一个步骤中连接到一个靶向基团，并在体外以松弛性和稳定性进行表征（目的1）。在啮齿动物模型中评估了高松弛性、稳定簇的钆解离和急性毒性，并将在小鼠胶质瘤模型中评估低剂量成像效果（Aim 2）。作为该技术平台的概念证明，我们使用在Aim 1中确定并在Aim 2中验证的稳定、高弛豫簇来证明这些试剂可以很容易地用于制备肽靶向分子成像探针（Aim 3）。我们在体内模型中使用这些试剂来对当前最先进的靶向MRI造影剂进行基准测试。在这个竞争性修订中，我们增加了第四个目标。一种替代非常高弛豫剂的方法是制备含有10s到1000s Gd螯合物的大分子。虽然这些大分子探针显著提高了检测灵敏度，但由于分子太大而无法通过肾脏的肾小球滤过器，它们受到Gd从体内不完全消除的限制。我们提出了一种构建含有10's稳定Gd螯合物的大分子的策略，该策略使用一种水解不稳定的连接体，允许大分子被控制地降解为更小的片段，这些片段在成像研究后完全从体内消除。我们将制备基于gd的大分子，并评估3种不同的水解不稳定连接剂。我们将在体外测量降解动力学，评估这些探针在小鼠体内的MR血管造影成像特性，并确定Gd从体内消除的速度和完全程度。总体目标是一种安全的大分子造影剂和广泛适用于MR分子成像应用的水解降解技术。

DESCRIPTION (provided by applicant): Stable, high relaxivity MRI contrast agents. Contrast agents play an important role in clinical magnetic resonance imaging (MRI). About one third of scans employ a contrast agent and these agents are almost exclusively gadolinium (Gd) based T1 agents that provide positive image contrast. Recently, however, Gd-based agents have been implicated in nephrogenic systemic fibrosis (NSF), a debilitating disorder that affects patients with renal insufficiency. It is hypothesized that Gd dissociated from the contrast agent is a causative factor. For new contrast agents, whether they are non-specific extracellular tracers or targeted molecular imaging agents, the risk of Gd toxicity must be addressed. One approach to this problem is to design better Gd ligands that are more resistant to Gd release. A second approach is to increase the relaxivity (r1), i.e. T1 relaxtion efficacy, of the contrast agent. High relaxivity agents could be given at lower doses, reducing metal ion exposure to the patient. The parent application combines both approaches synergistically to identify new, stable, high relaxivity contrast agents. The goal of the parent application is to develop chemically stable contrast agents that provide high relaxivity over a broad range of magnetic fields and that can be readily "plugged in" to targeting groups for molecular imaging. Clusters of potent, stable gadolinium-based complexes that can be linked to a targeting group in a single step are synthesized and characterized with respect to relaxivity and stability in vitro (Aim 1). High relaxivity, stable clusters are assessed in rodent models for gadolinium dissociation and acute toxicity, and will be evaluated in a mouse glioma model for low dose imaging efficacy (Aim 2). As a proof of concept for this technology platform, we use the stable, high relaxivity clusters identified in Aim 1 and validated in Aim 2 to demonstrate that these reagents can be used to readily prepare peptide-targeted molecular imaging probes (Aim 3). We use these agents in an in vivo model to benchmark against current state-of-the-art targeted MRI contrast agents. In this competitive revision we add a fourth aim. An alternative approach to very high relaxivity agents is to prepare macromolecules containing 10s to 1000s of Gd chelates. It well established that while these macromolecular probes have dramatically improved sensitivity of detection, they are limited by incomplete elimination of Gd from the body because the molecules are too large to pass through the glomerular filter in the kidneys. We propose a strategy of constructing macromolecules containing 10's of stable Gd chelates using a hydrolytically unstable linker that allows controlled degradation of the macromolecule to smaller fragments that are completely eliminated from the body after the imaging study. We will prepare Gd-based macromolecules and evaluate 3 different hydrolytically unstable linkers. We will measure the kinetics of degradation in vitro and evaluate the MR angiographic imaging properties of these probes in mice and determine how fast and completely the Gd is eliminated from the body. The overall goals are a safe macromolecular contrast agent and hydrolytic degradation technology that is broadly applicable to MR molecular imaging applications. PUBLIC HEALTH RELEVANCE: This project involves developing magnetic resonance imaging (MRI) probe technology. We will produce MRI probes that may be safer than existing probes and which are better suited to take advantage of advances in MRI hardware. These probes may be useful in detecting coronary artery disease and identifying cancerous lesions.