title: Gd-hydroxypyridinone (HOPO)-based high-relaxivity magnetic resonance imaging (MRI) contrast agents.
abstract: Magnetic resonance imaging (MRI) is a particularly effective tool in medicine because of its high depth penetration (from 1 mm to 1 m) and ability to resolve different soft tissues. The MRI signal is generated by the relaxation of in vivo water molecule protons. MRI images can be improved by administering paramagnetic agents, which increase the relaxation rates of nearby water protons, thereby enhancing the MRI signal. The lanthanide cation Gd(3+) is generally used because of its favorable electronic properties; high toxicity, however, necessitates strongly coordinating ligands to keep Gd(3+) completely bound while in the patient. In this Account, we give a coordination chemistry overview of contrast agents (CAs) based on Gd-hydroxypyridinone (HOPO), which show improved MRI contrast and high thermodynamic stabilities. Tris-bidentate HOPO-based ligands developed in our laboratory were designed to complement the coordination preferences of Gd(3+), especially its oxophilicity. The HOPO ligands provide a hexadentate coordination environment for Gd(3+), in which all of the donor atoms are oxygen. Because Gd(3+) favors eight or nine coordination, this design provides two to three open sites for inner-sphere water molecules. These water molecules rapidly exchange with bulk solution, hence affecting the relaxation rates of bulk water molecules. The parameters affecting the efficiency of these contrast agents have been tuned to improve contrast while still maintaining a high thermodynamic stability for Gd(3+) binding. The Gd-HOPO-based contrast agents surpass current commercially available agents because of a higher number of inner-sphere water molecules, rapid exchange of inner-sphere water molecules via an associative mechanism, and a long electronic relaxation time. The contrast enhancement provided by these agents is at least twice that of commercial contrast agents, which are based on polyaminocarboxylate ligands. Advances in MRI technology have made significant contributions to the improvement of clinical diagnostics by allowing visualization of underlying pathology. However, understanding the mechanism of a disease at the molecular level requires improved imaging sensitivity. The ultimate goal is to visually distinguish between different disease targets or markers, such as enzymes, hormones, proteins, or small molecules, at biologically relevant concentrations (from micro- to nanomolar). Although MRI techniques can provide images of the organs and tissues in which these biomarkers are regulated, the high sensitivity required to visualize the biological targets within the tissues is currently lacking; contrast enhancements of 50-fold beyond current agents are required to achieve this goal. According to the theory of paramagnetic relaxation, the contrast enhancement can be further improved by slowing the tumbling rate of the MRI agent. Theoretically, this enhancement would be greater for contrast agents with an optimal rate of water exchange. The Gd-HOPO-based contrast agents have optimal water-exchange rates, whereas the commercial agents have slower non-optimal water-exchange rates; thus, the Gd-HOPO agents are ideal for attachment to macromolecules, which will slow down the tumbling rate and increase contrast. This strategy has been recently tested with the Gd-HOPO agents via covalent attachment to virus capsids, affording contrast enhancements 10-fold beyond commercial agents.
authors.affiliation: Chemistry Department, University of California, Berkeley, California 94720.
authors.forename: Ankona
authors.initials: A
authors.lastname: Datta
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Raymond
mesh_terms: D003287:Contrast Media / Q000737:chemistry*; D018360:Crystallography, X-Ray; D005682:Gadolinium / Q000737:chemistry*; D007089:Image Enhancement; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008280:Magnetics; D008968:Molecular Conformation; D011522:Protons; D011725:Pyridines / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D003287:Contrast Media; D008024:Ligands; D011522:Protons; D011725:Pyridines; C014047:hydroxypyridines; D014867:Water; D005682:Gadolinium