Stable, high relaxivity MRI contrast agents Abstract Contrast agents play an important role in clinical magnetic resonance imaging (MRI). About one third of scans employ a contrast agent and these agents are almost exclusively gadolinium (Gd) based T1 agents that provide positive image contrast. However, Gd-based agents have been implicated in nephrogenic systemic fibrosis (NSF), a debilitating and life threatening disorder. It is hypothesized that Gd release from the contrast agent is a causative factor. New contrast agents, either extracellular tracers or targeted molecular imaging agents, must address the risk of Gd toxicity. Two additional features are required to make this new contrast agent technology broadly applicable today and in the future. First, although the majority of clinical scans today ar performed at 1.5 Tesla, there is a steady increase in imaging performed at higher fields. T1 relaxivity (positive contrast) typically decreases with increasing field while T2 relaxation (signa loss) becomes more efficient. Successful strategies for increasing r1 at low fields can be detrimental at high fields. New agents should demonstrate improved relaxivity from 1.5T to 7T and higher fields relative to existing contrast media. Second, new applications in molecular imaging require bifunctional molecules: a targeting group like a peptide linked to contrast agent group. New contrast agents should be easily incorporated into molecular imaging probes without loss of their relaxometric properties. We have developed a platform technology based on the amino acid chelator DOTAla that addresses this problem in two ways. The DOTAla moiety is a macrocyclic chelator that forms Gd complexes that are extremely inert to decomplexation and transmetallation, and is comparable to the macrocyclic contrast agents used clinically in this regard. The Gd-DOTAla complex can be incorporated into peptides in a rigid fashion in order to generate contrast agents that have high relaxivity as a result of optimized correlation times and increased gadolinium content per molecule. Because DOTAla is an amino acid, the synthetic flexibility in creating multimeric, targeted, and/or multimodal probes is unlimited. Here we build on this technology platform to develop optimized bifunctional reagents that deliver enhanced relaxivity at high fields.
In Aim 1 we take three complimentary approaches to synthesize compounds with enhanced relaxivity.
In Aim 2 we will perform extensive biophysical characterization of the compounds prepared in Aim 1 using advanced magnetic resonance and computational techniques in order to create models that prospectively predict new compounds with optimized dynamics and relaxivity. We then demonstrate the broader utility of this optimized technology platform by preparing untargeted (Aim 3) and peptide-targeted (Aim 4) high relaxivity contrast agents, and characterize them in rodent models of brain cancer and stroke.

Public Health Relevance

This project involves developing magnetic resonance (MR) imaging probe technology. We will produce MR probes that may be safer than existing probes, provide greater MR signal and which are better suited to take advantage of advances in MR hardware. The technology that we are developing can be readily used by others to prepare new imaging probes for imaging specific organs or diseases.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Project (R01)
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Clinical Molecular Imaging and Probe Development (CMIP)
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Conroy, Richard
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Massachusetts General Hospital
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Pierre, Valérie C; Allen, Matthew J; Caravan, Peter (2014) Contrast agents for MRI: 30+ years and where are we going? J Biol Inorg Chem 19:127-31
Boros, Eszter; Karimi, Shima; Kenton, Nathaniel et al. (2014) Gd(DOTAlaP): exploring the boundaries of fast water exchange in gadolinium-based magnetic resonance imaging contrast agents. Inorg Chem 53:6985-94
Motola, Daniel L; Caravan, Peter; Chung, Raymond T et al. (2014) Noninvasive Biomarkers of Liver Fibrosis: Clinical Applications and Future Directions. Curr Pathobiol Rep 2:245-256
Boros, Eszter; Caravan, Peter (2013) Structure-relaxivity relationships of serum albumin targeted MRI probes based on a single amino acid Gd complex. J Med Chem 56:1782-6
Polasek, Miloslav; Caravan, Peter (2013) Is macrocycle a synonym for kinetic inertness in Gd(III) Complexes? Effect of coordinating and noncoordinating substituents on inertness and relaxivity of Gd(III) chelates with DO3A-like ligands. Inorg Chem 52:4084-96
Sosnovik, David E; Caravan, Peter (2013) Molecular MRI of the Cardiovascular System in the Post-NSF Era. Curr Cardiovasc Imaging Rep 6:61-68
Fuchs, Bryan C; Wang, Huifang; Yang, Yan et al. (2013) Molecular MRI of collagen to diagnose and stage liver fibrosis. J Hepatol 59:992-8
Gale, Eric M; Kenton, Nathaniel; Caravan, Peter (2013) [Gd(CyPic3A)(H2O)2]-: a stable, bis(aquated) and high-relaxivity Gd(III) complex. Chem Commun (Camb) 49:8060-2
Moriggi, Loick; Yaseen, Mohammad A; Helm, Lothar et al. (2012) Serum albumin targeted, pH-dependent magnetic resonance relaxation agents. Chemistry 18:3675-86
Yang, Yan; Schuhle, Daniel T; Dai, Guangping et al. (2012) 1H chemical shift magnetic resonance imaging probes with high sensitivity for multiplex imaging. Contrast Media Mol Imaging 7:276-9

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