BLOOD POOL CONTRAST AGENTS FOR CT AND MRI

描述(改编自申请者摘要)：调查人员提出一个 他们将合成和测试一类新的血池制剂的项目 用于计算机断层扫描(CT)和磁共振(MR)成像。这项建议 包括初步数据，表明建议的代理增强了CT 肝脏血管的可视化和提供肿瘤血管的MR检测 在很长一段时间内。建议的代理是基于一种分子 葡聚糖骨架，Gd-DTPA的多个报告单元共价连接 附在这里。使用葡聚糖作为分子骨架提供了许多优点。 首先，该制剂不是粒子这一事实应该增加生物 安全。其次，葡聚糖有多种相对分子质量；这 将使优化试剂的血液停留时间和肿瘤成为可能 渗透性。第三，葡聚糖由重复的葡萄糖单位组成，每个单位 每个Gd-DOTA报告单元有三个潜在的附着点。 此属性将允许对代理进行优化。第四，广泛性 人类使用葡聚糖的经验增加了该试剂 注意安全。其目标是开发一种新型的显像剂，具有 用于检测肿瘤和其他组织病理学的适当属性 由异常的组织血管引起的。这些属性包括足够的 血液增强，良好的血液滞留时间，化学药品 体内外稳定性好，血浆特异性高。该项目已 五个具体目标。1)第一个是增强级别，它将提供 肝血管的信号比肝组织强两倍.之后 -01和B02，a.兔的CT和MR影像初步研究 将使用交叉设计来比较CT和MR成像特性 新的、优化的试剂与标准造影剂的那些。2)血浆 通过选择葡聚糖的大小和大小，可以实现一小时的半程时间 记者密度。初步数据表明，葡聚糖主链将成为 分子量为10克/摩尔，报告密度为两个Gd-DOTA单位 葡萄糖应该可以实现这一目标。将使用以下方法测量等离子体清晰度 Gd-153和C-14标记试剂。3)验证Gd-络合物的稳定性； 研究人员将测试体外稳定性和解离惯性。4) 研究人员将使用放射性标记技术测量毒剂的生物分布 成分(Gd-153，C-14-DOTA，C-14-甲基-葡聚糖，和S-35标签 Dota-to-Degan皮带)。5.在为期4年的项目中，调查人员将 放大合成并最大限度地提高记者密度。在完成时 这个项目，必要的信息将可用来确定 作为一种新的CT和MR成像血池试剂的临床潜力。这位代理 有望为癌症检测和分期提供更高的灵敏度， 更高的成像灵活性，以及更高的患者舒适度。此外，这一点 结构将作为未来一类非颗粒物的神经载体 受体结合型CT和MR造影剂。

DESCRIPTION (Adapted from Applicant's Abstract): The investigators propose a project in which they will synthesize and test a new class of blood pool agents for computed tomography (CT) and magnetic resonance (MR) imaging. The proposal includes preliminary data demonstrating that the proposed agent enhanced CT visualization of hepatic vessels and provided MR detection of tumor vasculature for an extended period of time. The proposed agent is based on a molecular backbone of dextran to which multiple reporter units of Gd-DTPA are covalently attached. Using dextran as a molecular backbone offers many advantages. First, the fact that the agent is not a particle should increase biological safety. Second, dextran is available in a variety of molecular weights; this will make it possible to optimize the agent's blood residence time and tumor permeability. Third, dextran is composed of repeating glucose units, each of which has three potential attachment sites fore each Gd-DOTA-reporter unit. This property will permit optimization of the agent. Fourth, the extensive human use experience with dextran increases the probability that the agent will be safe. The objective is to develop a new class of imaging agent with the appropriate attributes for detection of tumors and other tissue pathology resulting from abnormal tissue vascularity. These attributes include adequate blood enhancement, favorable residence time within the blood, chemical stability in vitro and in vivo, and high plasma specificity. The project has five specific aims. 1) The first is a level of enhancement that will give hepatic vessels a twofold greater signal than hepatic tissue. After preliminary CT and MR imaging studies in rabbits during the Years-01 and B02, a crossover design will be used to compare the CT and MR imaging properties of the new, optimized agent with those of standard contrast media. 2) Plasma half-time of one hour will be achieved by selection of dextran size and reporter density. Preliminary data indicate that a dextran backbone will a molecular weight of 10 g/mole and a reporter density of two Gd-DOTA units per glucose should accomplish this goal. Plasma clearance will be measured using Gd-153- and C-14-labeled agents. 3) To verify the stability of the Gd-complex; the investigators will test in vitro stability and dissociation inertia. 4) The investigators will measure the agent's biodistribution using radiolabeled components (Gd-153, C-14-DOTA, C-14-methyl-dextran, and a S-35 label for the Dota-to-dextran leash). 5. During the 4-year project the investigators will scale-up the synthesis and maximize reporter densities. At the completion of this project, the necessary information will be available to determine the clinical potential as a new blood pool agent for CT and MR imaging. This agent is expected to provide increased sensitivity for cancer detection and staging, greater imaging flexibility, and increased patient comfort. Additionally, this structure will serve as a neural carrier of for future class of nonparticulate receptor-binding CT and MR contrast media.