Contrast agents are often used in magnetic resonance imaging (MRI) studies to enhance contrast between tissues. During the last decade, a new type of contrast mechanism based on chemical exchange saturation transfer (CEST) has been explored using a variety of diamagnetic and paramagnetic molecules. Many endogenous molecules containing exchangeable –OH protons have been explored as potential CEST agents, including glucose and glycogen. Lactate also has an exchangeable –OH proton that could potentially be detected by CEST but the chemical shift of the lactate –OH proton is even closer to water than the –OH protons of glucose. Hence, it is quite difficult to detect lactate directly using CEST activation pulses. L-lactate is overproduced by most tumors even in the presence of abundant oxygen (the Warburg effect) so a method for direct imaging of lactate production by tumors could be a useful biomarker. We demonstrate here that one can shift the –OH resonance of L-lactate far downfield from tissue water protons using a well known Eu<sup>3+</sup>-based paramagnetic shift reagent (SR) and then use the “on” versus “off” CEST response to quantify lactate produced by tumor cells growing in tissue culture (Figure 1). Depending upon which paramagnetic complex is used, the shifts can be quite large (40-50 ppm), moving the CEST signal of lactate well away from other confounding endogenous signals from tissues. Interestingly, the intensity of the lactate CEST signal is enhanced at slightly acidic conditions (similar to that produced by tumors) and is higher at 37°C than at 25°C. The potential of the SR was demonstrated by imaging excess lactate excreted into the bladder of a mouse. These results provide the framework to develop and optimize new SRs to image lactate production in tumors by MRI.

Imaging L-lactate by CEST using paramagnetic shift reagents

253rd National Meeting (2017)

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