Investigation of hyperpolarized substrate metabolism has been showing utility in real‐time determination of in‐cell and in vivo enzymatic activities. Intracellular reaction rates may vary during the course of a measurement, even on the very short time scales of visibility on hyperpolarized MR, due to many factors such as the availability of the substrate and co‐factors in the intracellular space. Despite this potential variation, the kinetic analysis of hyperpolarized signals typically assumes that the same rate constant (and in many cases, the same rate) applies throughout the course of the reaction as observed via the build‐up and decay of the hyperpolarized signals. We demonstrate here an acquisition approach that can null the need for such an assumption and enable the detection of instantaneous changes in the rate of the reaction during an ex vivo hyperpolarized investigation, (i.e. in the course of the decay of one hyperpolarized substrate dose administered to a viable tissue sample ex vivo). This approach utilizes hyperpolarized product selective saturating‐excitation pulses. Similar pulses have been previously utilized in vivo for spectroscopic imaging. However, we show here favorable consequences to kinetic rate determinations in the preparations used. We implement this acquisition strategy for studies on perfused tissue slices and develop a theory that explains why this particular approach enables the determination of changes in enzymatic rates that are monitored via the chemical conversions of hyperpolarized substrates. Real‐time changes in intracellular reaction rates are demonstrated in perfused brain, liver, and xenograft breast cancer tissue slices and provide another potential differentiation parameter for tissue characterization.
Deuteration of the exchangeable hydrogens of [ N ]urea was found to prolong the T of the N sites to more than 3 min at physiological temperatures. This significant increase in the lifetime of the hyperpolarized state of [ N ]urea, compared to [ C]urea - a pre-clinically proven perfusion agent, makes [ N ]urea a promising perfusion agent. The molecular parameters that may lead to this profound effect were assessed by investigating small molecules with different molecular structures containing N sites bound to labile protons and determining the hyperpolarized N T in H O and D O. Dissolution in D O led to marked prolongation for all of the selected sites. In whole human blood, the T of [ N ]urea was shortened. We present a general strategy for exploiting the markedly longer T outside the body and the quick decay in blood for performing multiple hyperpolarized perfusion measurements with a single hyperpolarized dose. Improved storage of the generated [ N ]urea polarization prior to the contact with the blood is demonstrated using higher temperatures due to further T prolongation.
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