Stable High Relaxivity MRI Contrast Agents

描述（由申请人提供）：稳定、高弛豫率MRI造影剂。对比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，这些造影剂几乎完全是基于钆（Gd）的T1造影剂，其提供正图像对比度。然而，最近，Gd为基础的药物已牵连在肾源性系统性纤维化（NSF），一个衰弱的疾病，影响患者的肾功能不全。假设Gd从造影剂中解离是一个致病因素。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，都必须解决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，其对Gd释放更有抗性。第二种方法是增加造影剂的弛豫率（r1），即T1弛豫功效。高弛豫剂可以以较低的剂量给予，减少金属离子对患者的暴露。母申请将两种方法协同结合以识别新的、稳定的、高弛豫率造影剂。母申请的目标是开发化学稳定的造影剂，其在宽范围的磁场内提供高弛豫率，并且可以容易地“插入”靶向基团用于分子成像。合成了可以在单个步骤中连接到靶向基团的有效的、稳定的钆基复合物的簇，并在体外表征了弛豫性和稳定性（目的1）。在啮齿动物模型中评估高弛豫率、稳定簇的钆解离和急性毒性，并将在小鼠神经胶质瘤模型中评估低剂量成像功效（目的2）。作为该技术平台的概念证明，我们使用目标1中鉴定并在目标2中验证的稳定的高弛豫率簇来证明这些试剂可用于容易地制备肽靶向分子成像探针（目标3）。我们在体内模型中使用这些药物，以目前最先进的靶向MRI造影剂为基准。在这个竞争性的修订中，我们增加了第四个目标。获得非常高弛豫率试剂的替代方法是制备含有10s至1000s Gd螯合物的大分子。已经确定，虽然这些大分子探针显著提高了检测灵敏度，但它们受到Gd从体内不完全消除的限制，因为分子太大而不能通过肾脏中的肾小球过滤器。我们提出了一种构建含有10个稳定Gd螯合物的大分子的策略，该策略使用水解不稳定的连接体，该连接体允许大分子受控降解为在成像研究后完全从体内消除的较小片段。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体。我们将测量体外降解动力学，并评估这些探针在小鼠中的MR血管造影成像特性，并确定Gd从体内消除的速度和程度。总体目标是一种安全的大分子造影剂和水解降解技术，广泛适用于MR分子成像应用。 公共卫生相关性：该项目涉及开发磁共振成像（MRI）探头技术。我们将生产可能比现有探头更安全的MRI探头，并且更适合利用MRI硬件的进步。这些探针可能有助于检测冠状动脉疾病和识别癌性病变。

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.