BLOOD POOL CONTRAST AGENTS FOR CT AND MRI

描述（改编自申请人摘要）：研究人员提出了一个 他们将合成和测试一类新的血池剂的项目 用于计算机断层扫描（CT）和磁共振（MR）成像。 该提案 包括初步数据，表明拟议的代理人增强CT 肝血管可视化，并提供肿瘤血管的MR检测 在很长一段时间内。 所提出的代理是基于一种分子 Gd-DTPA的多个报告单元共价连接到葡聚糖的骨架上 附 使用葡聚糖作为分子骨架提供了许多优点。 首先，该制剂不是颗粒的事实应该增加生物活性。 安全为代价的 其次，右旋糖酐可以以各种分子量获得;这 将使优化药剂的血液停留时间和肿瘤 磁导率 第三，葡聚糖由重复的葡萄糖单元组成，每个葡萄糖单元 其在每个Gd-DOTA-报告单元上具有三个潜在的附着位点。 此属性将允许优化代理。 第四，广泛 人类使用右旋糖酐的经验增加了该试剂 注意安全 目的是开发一类新的显像剂， 用于检测肿瘤和其他组织病理学的适当属性 由异常的组织血管分布引起。 这些属性包括： 血液增强，在血液中有利的停留时间，化学 体内外稳定性好，血浆特异性高。 该项目 五个具体目标。 1)第一个是增强级别， 肝血管的信号比肝组织高两倍。 后 在01年和B 02年期间对兔子进行的初步CT和MR成像研究，a 交叉设计将用于比较以下各项的CT和MR成像特性： 新的，优化的代理与标准造影剂。 2)血浆 通过选择右旋糖酐的大小可以达到1小时的半衰期， 报告基因密度 初步数据表明，葡聚糖骨架将是一种 分子量为10克/摩尔，报道分子密度为每摩尔两个Gd-DOTA单元， 葡萄糖应该可以实现这一目标。 血浆清除率将使用 Gd-153和C-14标记的试剂。 3)验证Gd配合物的稳定性; 研究人员将测试体外稳定性和解离惯性。 四、 研究人员将使用放射性标记的 组分（Gd-153、C-14-DOTA、C-14-甲基-葡聚糖和用于所述化合物的S-35标记物）。 Dota-to-dextran皮带）。 5. 在为期4年的项目中，研究人员将 放大合成并最大化报告分子密度。 完成时 这个项目，必要的信息将可用于确定 作为CT和MR成像的新血池剂的临床潜力。 此代理 有望为癌症检测和分期提供更高的灵敏度， 更大的成像灵活性和更高的患者舒适度。 而且这个 结构将作为未来非微粒类神经载体 受体结合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.