Using Two Chemical Exchange Saturation Transfer Magnetic Resonance Imaging Contrast Agents for Molecular Imaging Studies

Abstract

CONSPECTUS Responsive magnetic resonance imaging (MRI) contrast agents can change MR image contrast in response to a molecular biomarker. Quantitative detection of the biomarker requires an accounting of the other effects that may alter MR image contrast, such as a change in the agent’s concentration, magnetic field variations, and hardware sensitivity profiles. A second unresponsive MRI contrast agent may serve as an “internal control” to isolate the detection of the molecular biomarker. Chemical exchange saturation transfer (CEST) MRI contrast agents can be selectively detected, providing the opportunity to combine a responsive CEST agent and an unresponsive CEST agent during the same MRI scan session. When two CEST MRI contrast agents are used for molecular imaging applications, the CEST agents should be designed to maximize accurate quantification of the concentrations of the two agents. From a chemical perspective, CEST agents behave like enzymes that catalyze the conversion of an unsaturated water “substrate” into a saturated water “product”. The analysis of CEST agent kinetics parallels the Michaelis–Menten analysis of enzyme kinetics, which can be used to correlate the CEST effect with the concentration of the agent in solution. If the concentration of water “substrate” that is available to the CEST agent is unknown, which may be likely for in vivo MRI studies, then only a ratio of concentrations of the two CEST agents can be measured. In both cases, CEST agents should be designed with minimal T1 relaxivity to improve concentration quantifications. CEST agents can also be designed to maximize sensitivity. This may be accomplished by incorporating many CEST agents within nanoparticles to create a large number of exchangeable protons per nanoparticle. Finally, CEST agents can be designed with rapid detection in mind. This may be accomplished by minimizing T1 relaxivity of the CEST agent so that MRI acquisition methods have time to collect many MRI signals following a single selective saturation period. In this Account, we provide an example that shows the sensitive and rapid detection of two CEST agents in an in vivo MRI study of a mouse model of mammary carcinoma. The ratio of the concentrations of the two CEST agents was quantified with analysis methods that parallel Michaelis–Menten enzyme kinetic analysis. This example demonstrates current limitations of the method that require additional research, but it also shows that two CEST MRI contrast agents can be detected and quantitatively assessed during in vivo molecular imaging studies.

A single diamagnetic catalyCEST MRI contrast agent that detects cathepsin B enzyme activity by using a ratio of two CEST signals

“…6) (16). Even at a low concentration of 3.125 mM, the salicylic acid generated a 8.6% CEST signal and the aryl amide generated a 4.4% CEST signal.…”

Rare earths: jewels for functional materials of the future

“…42 The advent of the chemical exchange saturation transfer technique (CEST) has also brought a new dimension to resonance magnetic bioanalyses. 43,44 However, optical bioprobes are gaining momentum because when appropriate wavelengths are used their penetration depth may be substantial, allowing the detection of analytes and biomarkers in cells and tissues which are not detectable by other techniques. 3,45 The contribution of lanthanides to these aspects started more than 30 years ago with luminescent time-resolved immunoassays and is now omnipresent, judging by the impressive number of papers devoted to this type of research as well as of review articles.…”

Quantification of iopamidol multi-site chemical exchange properties for ratiometric chemical exchange saturation transfer (CEST) imaging of pH

“…Because the labile proton concentration has to be independently determined in order to derive pH, the conventional CEST imaging only provides pH-weighted information (Sun, 2010b; Zu et al , 2012; Sun et al , 2013b). To address this limitation, ratiometric CEST MRI has been proposed that normalizes the confounding concentration effect for simplifying pH measurement (Ward and Balaban, 2000; Ali et al , 2009; Liu et al , 2012). A particularly interesting ratiometric MRI agent is iopamidol, approved by food and drug administration (FDA) as a X-Ray contrast agent since 1980s, which has been recently shown capable of imaging renal pH (Longo et al , 2012; Longo et al , 2011; Aime et al , 2005).…”