Purpose

To develop a specialized multislice, single-acquisition approach to detect the metabolites of hyperpolarized (HP) [2-¹³ C]dihydroxyacetone (DHAc) to probe gluconeogenesis in vivo, which have a broad 144 ppm spectral range (∼4.6 kHz at 3T). A novel multiband radio-frequency (RF) excitation pulse was designed for independent flip angle control over five to six spectral-spatial (SPSP) excitation bands, each corrected for chemical shift misregistration effects.

Methods

Specialized multiband SPSP RF pulses were designed, tested, and applied to investigate HP [2-¹³ C]DHAc metabolism in kidney and liver of fasted rats with dynamic ¹³ C-MR spectroscopy and an optimal flip angle scheme. For comparison, experiments were also performed with narrow-band slice-selective RF pulses and a sequential change of the frequency offset to cover the five frequency bands of interest.

Results

The SPSP pulses provided a controllable spectral profile free of baseline distortion with improved signal to noise of the metabolite peaks, allowing for quantification of the metabolic products. We observed organ-specific differences in DHAc metabolism. There was two to five times more [2-¹³ C]phosphoenolpyruvate and about 19 times more [2-¹³ C]glycerol 3-phosphate in the liver than in the kidney.

Conclusion

A multiband SPSP RF pulse covering a spectral range over 144 ppm enabled in vivo characterization of HP [2-¹³ C]DHAc metabolism in rat liver and kidney. Magn Reson Med 77:1419-1428, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

The purpose of this study was to investigate the feasibility of in vivo ¹³ C->¹ H hyperpolarization transfer, which has significant potential advantages for detecting the distribution and metabolism of hyperpolarized ¹³ C probes in a clinical MRI scanner.

Methods

A standalone pulsed ¹³ C RF transmit channel was developed for operation in conjunction with the standard ¹ H channel of a clinical 3T MRI scanner. Pulse sequences for ¹³ C power calibration and polarization transfer were programmed on the external hardware and integrated with a customized water-suppressed ¹ H MRS acquisition running in parallel on the scanner. The newly developed RF system was tested in both phantom and in vivo polarization transfer experiments in ¹ J_CH -coupled systems: phantom experiments in thermally polarized and hyperpolarized [2-¹³ C]glycerol, and ¹ H detection of [2-¹³ C]lactate generated from hyperpolarized [2-¹³ C]pyruvate in rat liver in vivo.

Results

Operation of the custom pulsed ¹³ C RF channel resulted in effective ¹³ C->¹ H hyperpolarization transfer, as confirmed by the characteristic antiphase appearance of ¹ H-detected, ¹ J_CH -coupled doublets. In conjunction with a pulse sequence providing 190-fold water suppression in vivo, ¹ H detection of hyperpolarized [2-¹³ C]lactate generated in vivo was achieved in a rat liver slice.

Conclusion

The results show clear feasibility for effective ¹³ C->¹ H hyperpolarization transfer in a clinical MRI scanner with customized heteronuclear RF system.

Purpose

To investigate acute changes in glucose metabolism in liver and kidneys in vivo after a bolus injection of either fructose or glucose, using hyperpolarized [2-¹³ C]dihydroxyacetone.

Methods

Spatially registered, dynamic, multislice MR spectroscopy was acquired for the metabolic products of [2-¹³ C]dihydroxyacetone in liver and kidneys. Metabolism was probed in 13 fasted rats at three time points: 0, 70, and 140 min. At 60 min, rats were injected intravenously with fructose (n = 5) or glucose (n = 4) at 0.8 g/kg to initiate acute response. Controls (n = 4) did not receive a carbohydrate challenge.

Results

Ten minutes after fructose infusion, levels of [2-¹³ C]phosphoenolpyruvate and [2-¹³ C]glycerol-3-phosphate halved in liver: 51% (P = 0.0010) and 47% (P = 0.0001) of baseline, respectively. Seventy minutes later, levels returned to baseline. The glucose challenge did not alter the signals significantly, nor did repeated administration of the dihydroxyacetone imaging bolus. In kidneys, no statistically significant changes were detected after sugar infusion other than a 20% increase of the glycerol-3-phosphate signal between 10 and 80 min after fructose injection (P = 0.0028).

Conclusion

Hyperpolarized [2-¹³ C]dihydroxyacetone detects a real-time, transient metabolic response of the liver to an acute fructose challenge. Observed effects possibly include ATP depletion and changes in the unlabeled pool sizes of glycolytic intermediates. Magn Reson Med 77:65-73, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Purpose

Although ¹ H spin coupling is generally avoided in probes for hyperpolarized (HP) ¹³ C MRI, enzymatic transformations of biological interest can introduce large ¹³ C-¹ H couplings in vivo. The purpose of this study was to develop and investigate the application of ¹ H decoupling for enhancing the sensitivity for detection of affected HP ¹³ C metabolic products.

Methods

A standalone ¹ H decoupler system and custom concentric ¹³ C/¹ H paddle coil setup were integrated with a clinical 3T MRI scanner for in vivo ¹³ C MR studies using HP [2-¹³ C]dihydroxyacetone, a novel sensor of hepatic energy status. Major ¹³ C-¹ H coupling J_CH  = ∼150 Hz) is introduced after adenosine triphosphate-dependent enzymatic transformation of HP [2-¹³ C]dihydroxyacetone to [2-¹³ C]glycerol-3-phosphate in vivo. Application of WALTZ-16 ¹ H decoupling for elimination of large ¹³ C-¹ H couplings was first tested in thermally polarized glycerol phantoms and then for in vivo HP MR studies in three rats, scanned both with and without decoupling.

Results

As configured, ¹ H-decoupled ¹³ C MR of thermally polarized glycerol and the HP metabolic product [2-¹³ C]glycerol-3-phosphate was achieved at forward power of approximately 15 W. High-quality 3-s dynamic in vivo HP ¹³ C MR scans were acquired with decoupling duty cycle of 5%. Application of ¹ H decoupling resulted in sensitivity enhancement of 1.7-fold for detection of metabolic conversion of [2-¹³ C]dihydroxyacetone to HP [2-¹³ C]glycerol-3-phosphate in vivo.

Conclusions

Application of ¹ H decoupling provides significant sensitivity enhancement for detection of HP ¹³ C metabolic products with large ¹ H spin couplings, and is therefore expected to be useful for preclinical and potentially clinical HP ¹³ C MR studies. Magn Reson Med 80:36-41, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

This white paper discusses prospects for advancing hyperpolarization technology to better understand cancer metabolism, identify current obstacles to HP (hyperpolarized) ¹³C magnetic resonance imaging's (MRI's) widespread clinical use, and provide recommendations for overcoming them. Since the publication of the first NIH white paper on hyperpolarized ¹³C MRI in 2011, preclinical studies involving [1-¹³C]pyruvate as well a number of other ¹³C labeled metabolic substrates have demonstrated this technology's capacity to provide unique metabolic information. A dose-ranging study of HP [1-¹³C]pyruvate in patients with prostate cancer established safety and feasibility of this technique. Additional studies are ongoing in prostate, brain, breast, liver, cervical, and ovarian cancer. Technology for generating and delivering hyperpolarized agents has evolved, and new MR data acquisition sequences and improved MRI hardware have been developed. It will be important to continue investigation and development of existing and new probes in animal models. Improved polarization technology, efficient radiofrequency coils, and reliable pulse sequences are all important objectives to enable exploration of the technology in healthy control subjects and patient populations. It will be critical to determine how HP ¹³C MRI might fill existing needs in current clinical research and practice, and complement existing metabolic imaging modalities. Financial sponsorship and integration of academia, industry, and government efforts will be important factors in translating the technology for clinical research in oncology. This white paper is intended to provide recommendations with this goal in mind.