Rapid sequential injections of hyperpolarized [1-13C]pyruvate in vivo using a sub-kelvin, multi-sample DNP polarizer

Abstract

The development of hyperpolarized technology utilizing dynamic nuclear polarization (DNP) has enabled the rapid measurement of 13C metabolism in vivo with very high SNR. However, with traditional DNP equipment, consecutive injections of a hyperpolarized compound in an animal have been subject to a practical minimum time between injections governed by the polarization build-up time, which is on the order of an hour for [1-13C]pyruvate. This has precluded the monitoring of metabolic changes occurring on a faster time scale. In this study, we demonstrated the ability to acquire in vivo dynamic magnetic resonance spectroscopy (MRS) and 3D magnetic resonance spectroscopic imaging (MRSI) data in normal rats with a 5 minute interval between injections of hyperpolarized [1-13C]pyruvate using a prototype, sub-Kelvin dynamic nuclear polarizer with the capability to simultaneously polarize up to 4 samples and dissolve them in rapid succession. There were minimal perturbations in the hyperpolarized spectra as a result of the multiple injections, suggesting that such an approach would not confound the investigation of metabolism occurring on this time scale. As an initial demonstration of the application of this technology and approach for monitoring rapid changes in metabolism as a result of a physiological intervention, we investigated the pharmacodynamics of the anti-cancer agent dichloroacetate (DCA), collecting hyperpolarized data before administration of DCA, 1 minute after administration, and 6 minutes after administration. Dramatic increases in 13C-bicarbonate were detected just 1 minute (as well as 6 minutes) after DCA administration.

Technique development of 3D dynamic CS‐EPSI for hyperpolarized 13C pyruvate MR molecular imaging of human prostate cancer

“…Lactate and alanine production was also found in rat liver (data not shown). These outcomes were highly consistent with the previous observations on HP‐ 13 C rat studies …”

Development of high resolution 3D hyperpolarized carbon-13 MR molecular imaging techniques

“…[ 13 C, 15 N 2 ]Urea (Sigma Aldrich) was dissolved in glycerol and mixed with 15 mM trityl radical OX063 (Oxford Instruments, Abingdon, UK) and 1.5 mM Gd-DOTA. Each compound was individually polarized in either a HyperSense dissolution DNP system (Oxford Instruments, Abingdon, UK) operating at 1.35 K and 3.35 T (lactic acid [41] and urea [22]) for ~1hr or a SpinLab (GE Healthcare, Waukesha, WI), operating at 0.8K and 3.35T (pyruvic acids [42]) for ~2hrs to achieve polarizations of 20–25% (urea and lactate) to 30–35% (pyruvic acids). The dissolution media and resulting concentration for each compound was as follows: 4.5 mL of 80 mM NaOH/40 mM Tris buffer for [1- 13 C]pyruvic acid resulting in 80 mM [1- 13 C]pyruvate (hereafter referred to as C 1 -pyruvate); 4.5 mL of 80 mM NaOH/40 mM Tris buffer for [2- 13 C]pyruvic acid resulting in 80 mM [2- 13 C]pyruvate (hereafter referred to as C 2 -pyruvate); 4.5 mL of 160 mM NaOH/40 mM Tris buffer for [1- 13 C]lactic acid resulting in 160 mM [1- 13 C]lactate (hereafter referred to as lactate); 5mL of 1x phosphate-buffered saline for [ 13 C, 15 N 2 ]urea resulting in 110 mM [ 13 C, 15 N 2 ]urea (hereafter referred to as urea).…”

Dynamic hyperpolarized carbon‐13 MR metabolic imaging of nonhuman primate brain

“…The hyperpolarized [1‐ 13 C]‐pyruvate was produced using either a prototype SpinLab (General Electric, Niskayuna, New York, USA) or a HyperSense (Oxford Instruments, Abingdon, UK) DNP polarizer. For the SpinLab system, a mixture consisting of 1,000 μL (∼1,280 mg) of C1‐labeled pyruvic acid and 15 mM trityl radical was polarized.…”