It has recently become possible to obtain spatially resolved """"""""images"""""""" of the nuclear spins of biological and chemical materials. Magnetic resonance imaging (MRI) is rapidly evolving into an important tool for the clinical diagnosis of a wide range of human pathologies. Clinical MRI studies are increasingly relying on the use of supplemental """"""""contrast agents"""""""" to enhance the diagnostic value of these studies. Two classes of these agents, which act by altering nuclear relaxation properties, have been utilized: chelated paramagnetic ions, which have found widespread clinical applications, and stable organic nitroxide radicals. The use of such agents raises basic questions about the factors which determine their distribution and metabolism, as well as questions about short or long term toxicity. We have previously investigated the distribution of several of these agents, including bare transition metal ions, GD-DTPA, a chelated lanthanide compound which is currently in clinical use, and GdHAM, an experimental agent with a net positive charge. Agents were introduced intracerebrally to evaluate the potential diagnostic utility of this route of administration. Based on initial results suggesting that net charge may play an important role in determining the distribution of these compounds, a series of studies using both bare transition metal ions and CDTA chelated forms was carried out. The results provide strong support for the importance of charge in determining tissue distribution, with the adherence of unchelated transition metal ions as well as GdHAM to the luminal walls of the cerebral ventricles presumably related to the negatively charged sialic acid residues present in these structures. In a related series of studies, a series of stable nitroxides has been similarly administered intracerebrally. These agents are much more effective using this route of administration as a consequence of the minimal rate of reduction of these compounds in CSF, which contrasts sharply with the short lifetimes in blood and in cells. In these applications, significant contrast has been achieved, with the lifetime of the agents apparently related to their rate of transport across cell membranes.
