Gd−Hydroxypyridinone (HOPO)-Based High-Relaxivity Magnetic Resonance Imaging (MRI) Contrast Agents

Abstract

ConspectusMagnetic resonance imaging (MRI) is a particularly effective tool in medicine because of its high depth penetration (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 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 , following which he began his faculty appointment at UC Berkeley. His research interests encompass microbial iron transport, the development of actinide sequestration agents, lanthanide-based luminescent and MRI agents, and supra-molecular metal complex clusters for host-guest chemistry and catalysis. NIH Public Access Author ManuscriptAcc Chem Res. Author manuscript; available in PMC 2010 July 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 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 (millimolar 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 t...

The Synthesis and Molecular Structure of 1-(3,4-Dihydroxyphenethyl)-3-hydroxy-2-methylpyridin-4(1H)-one Hydrochloride Methanol Solvate

“…The two vinylic protons on the pyridinone ring appear as doublets with J HH = 7.2 Hz at δ 7.41 and 6.04 ppm. All solution spectroscopic data are consistent with previously prepared hydroxypyridinone derivatives that have a localized alkene within the ring and elemental analysis confirms the majority of the product is the neutral species [1][2][3]. However, we were able to obtain one single crystal of the hydrochloride salt for an X-ray diffraction study, the molecular structure of which is shown in Figure 2.…”

“…Hydroxypyridinones are an important class of heterocyclic compounds that are being examined as possible agents for sequestering and removing toxic metal ions [1][2][3]. For instance, Deferiprone (Figure 1b) belongs to a class of 3-hydroxy-4-pyridinone compounds derived from maltol ( Figure 1a), a natural flavor enhancer, which is being investigated for its use as a chelating agent for the treatment…”

The magnetic, relaxometric, and optical properties of gadolinium-catalyzed single walled carbon nanotubes

“…B. Relaxivity, nuclear magnetic dispersion profiles NMRD measurements provide valuable insights and information about the dynamic, and structural parameters of MRI CAs that influence relaxivity. [3][4][5]8 The r 1 NMRD profile (proton Larmor frequency ¼ 1.15 to 61.73 MHz) for proton relaxivity at 25 C for individually dispersed Gd-SWCNTs in 1% Pluronic F127 is presented in Figure 3(a). Gd-SWCNTs have distinctly different r 1 NMRD profiles than Gd 2 O 3 nanoparticles dispersed in 1% Pluronic F127 solution (Figure 3(b)), and Gd 3þ -based small molecular and macromolecular complexes.…”

“…7 Theoretical studies predict the possible development of novel MRI CAs with 50-100 times greater relaxivity than current clinical gadolinium-chelate complexes. 4,8 Thus, a major focus of MRI CA research has been to utilize relaxometry and other characterization tools to further understand the molecular, structural, dynamic, and magnetic properties of MRI CAs that affect water proton relaxation times. 8 This improved understanding facilitates the development of rational synthetic design strategies to improve the relaxivity of next-generation MRI CAs.…”

Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging

“…To address a critical, unmet medical need, we developed a strategy in our creation of an MRI contrast agent using protein design and modification to increase relaxivity without compromising metal binding affinity/stability, selectivity, and pharmacokinetic properties that are dramatically different from previously reported approaches (25)(26)(27)(28)(29)(30)(31)(32). Building on our previous success in improving relaxivity by designing a Gd 3+ -binding site into a scaffold protein CD2 and with a goal of improving metal binding affinity, we report a method to develop the protein contrast agent ProCA32 by converting the natural Ca 2+ -binding protein, parvalbumin, into a Gd 3+ -binding protein that is also PEGylated.…”