MRI Contrast Agents
Introduction
MRI enables the acquisition of high resolution, three-dimensional images of the distribution of water in vivo. These images are enhanced by the use of contrast agents that catalytically decrease the relaxation time of protons of water coordinated to a paramagnetic metal center. Gd(III), with 7 unpaired electrons and a long electronic relaxation time, is ideally suited for such agents. However, current Gd(III)-based commercial agents have very poor contrast enhancement capabilities due to their low relaxivity. Those agents are therefore limited to targeting sites where they can be expected to accumulate in high concentrations, such as in the blood stream and kidneys. The current challenge is to design contrast agents with higher relaxivities that will selectively localize in specific tissues or organs.
MRI scan of a mouse obtained with one of our complexes
functionalized with spleen targeting moieties.Raymond and coworkers have been working on hydroxypyridinone (HOPO) and mixed hydroxypyridinone-terephthalamide (HOPO-TAM) based complexes that show promise due to their higher relaxivity. This increase in relaxivity is due to both an increase in the number of coordinated water molecules and near-optimal water exchange rates. Low toxicity can be predicted for our complexes owing to the high selectivity of the HOPO and HOPO-TAM ligands for Gd(III) over physiologically available metals such as Zn(II) and Ca(II) as well as because of the high stability of the Gd(III) complexes in comparison to other favorable Gd(III) chelates. Work is currently in progress to further increase relaxivity using these ligand systems as well as to understand their advantageous water-exchange kinetics.
High relaxivity can be obtained by increasing q, optimizing τM, and slowing molecular tumbling (long τR). Jocher, C. J.; Botta, M.; Avedano, S.; Moore, E. G.; Xu, J.; Aime, S.; Raymond, K. N. "Optimized Relaxivity and Stability of [Gd(H(2,2)-1,2- HOPO)(H2O)]- for Use as MRI Contrast Agent." Inorg. Chem. 2007, 46, 4796-4798.
Pierre, V. C.; Botta, M.; Aime, S.; Raymond, K. N. "Substituent Effects on Gd(III)-Based MRI Contrast Agents: Optimizing the Stability and Selectivity of the Complex and the Number of Coordinated Water Molecules." Inorg. Chem. 2006, 45, 8355-8364.
For a short review: Raymond, K. N. and Pierre, V. C. "Next Generation, High Relaxivity Gadolinium MRI Agents." Bioconjugate Chem. 2005, 16, 3-8.
Macromoleculear MRI Contrast AgentsThe Solomon-Bloembergen-Morgan theory of paramagnetic relaxivity predicts that the relaxivity of a Gd(III) complex with optimally fast water exchange rate (kexch = 108 s-1) can be drastically increased upon slowing its molecular tumbling. This can be achieved by grafting the complex onto the periphery of large, rigid macromolecules such as dendrimers and proteins. The use of dendrimers enables us to control both the size of the molecule (and hence its tumbling) as well as the location of the complex on the macromolecule. The solubility of a dendrimer is primarily determined by its terminal groups. Since hydroxypyridinone-based Gd(III) complexes are hydrophobic, block dendrimers containing water-soluble moieties are being synthesized and studied.
Viral capsids provide a macromolecular nanosized scaffold for incorporation of imaging and targeting agents. Nano-sized contrast agents obtained by multiple attachment of a Gd(III) complex have the advantages of high per Gd and total molecular relaxivity and can therefore be used for targeted imaging of biomarkers that are present in low concentration in vivo. Recent work in the group (in collaboration with the Francis Group, UC Berkeley) has demonstrated that Gd(III) hydroxypyridonate based complexes can be covalently attached to the exterior and interior of empty MS2 virus capsids (devoid of nucleic acids). Up to 90 contrast agents per capsid have been installed, and per Gd relaxivities as high as 41.6 mM-1s-1 (298 K, 30 MHz) have been obtained. The results indicate that the internally modified capsids have higher relaxivities than the externally modified capsids, proving that facile water diffusion to the capsid interior is taking place. The internally modified capsids were also more soluble than the externally modified capsids and hence can be used to attach targeting groups on the exterior. The relaxivity enhancements seem to be affected by the rigidity of the covalent linker used for the attachment (i.e the more rigid the linker, the better relaxivity). Work is in progress to incorporate targeting groups on the exterior surface and improve the relaxivity further by using rigid linkers.
