BLOOD POOL CONTRAST AGENTS FOR CT AND MRI

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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.