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MRI Contrast Agents

More then 1.5 million new cases of cancer were projected for 2010.  To image in soft tissue and diagnose cancer, sports injuries, etc. without ioizing radiation, over 75 million MRI scans are performed per annum. To enhance diagnostic power, contrast agents to further distinguish healthy and pathological tissue are used in 30-40% of scans.

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 seven unpaired electrons and a long electronic relaxation time, is ideally suited for such agents. However, current Gd(III)-based commercial agents have inefficient 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 mouse injected with Gd-TREN-bis-(1-Me)-3,2-HOPO-TAM-PEG.

Thompson, M. K.; Misselwitz, B.; Tso, L. S.; Doble, D. M. J.; Schmitt-Willich, H.; Raymond, K. N. J. Med. Chem. 2005, 48, 3874-3877.

   Since 1995, the Raymond group has been working on optimizing HOPO chelators for MRI applications. Recent highlights have included mouse imaging (above) in 2005, bioconjugation to the viral capsid in 2007, expanded 1,2-HOPO library in 2009, and variation of the capping moiety in 2007 and 2009.  We have worked with hydroxypyridinone (HOPO) and mixed hydroxypyridinone-terephthalamide (HOPO-TAM) based complexes that show promise due to their high 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).

Short review articles:

Datta, A.; Raymond, K. N. Acc. Chem. Res. 2009, 42, 938–947.

Raymond, K. N.; Pierre, V. C. Bioconjugate Chem. 2005, 16, 3–8.

Werner, E. J.; Datta, A.; Jocher, C. J.; Raymond, K. N.  Angew. Chem., Int. Ed. 2008, 45, 8568-8580.

Macromolecular MRI Contrast Agents


The 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 conjugation the complex onto macromolecules, such as dendrimers developed by the Fréchet Group at University of California, Berkeley. Since hydroxypyridinone-based Gd(III) complexes are hydrophobic, block dendrimers containing water-soluble moieties are of special interest. The esteramide dendrimer (below) is unique because of its rapid excretion. While it is 40 kDa and holds eight Gd-HOPO complexes, the ester core hydrolyzes in vivo over several days, lending suitable renal clearance.

mripjk      mriden

Floyd, W.C. III; Klemm, P. J.; Smiles, D. E.; Kohlgruber, A. C.; Pierre, V. C.; Mynar, J. L.; Frechét, J. M. J.; Raymond, K. N. J. Am. Chem. Soc. 2011, 133, 2390-2393.

Klemm, P. J.; Floyd, W.C. III; Smiles, D.E.; Fréchet, J. M. J.; Raymond, K. N. Contrast Media Mole Imaging. Accepted.

Compounds 1-4 have been successfully conjugated to the esteramide dendrimer, with 1 exhibiting the highest relaxivity. Right: The esteramide dendrimer conjugated to Gd-TACN-bis-(1-Me)-3,2-HOPO-TAM-ethylamine. All complexes conjugated to the esteramide dendrimer exhibit increased relaxivity, increased solubility, no toxicity to HeLa cells over 72 h, no aggregation by dynamic light scattering (DLS) and no small molecule impurities by UV-Vis size exclusion chromatography.

Viral capsids also provide a macromolecular nanosized scaffold for incorporation of imaging and targeting agents. Nano-sized contrast agents obtained by multiple attachments of a Gd(III) complex have the advantages of high per Gd and total molecular relaxivity and can therefore be used for low concentration in vivo targeted imaging of biomarkers. Previous work in the group (in collaboration with the Francis Group, UC Berkeley) 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. 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 were thought to be affected by the rigidity of the covalent linker used for the attachment. This work was continued and showed that the rigidity of the linker associated with a specific spatial orientation to the surface of the viral capsids, that allowed an increase in water accessibility, gave rise to an enhancement of the relaxivity compared to a rigid linker that beared the Gd(III) complex close to the surface of the nano-support.



                        This project is supported by funding from the National Institute of Health.

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