Metabolite-specific echo-planar imaging (EPI) sequences with spectral-spatial (spsp) excitation are commonly used in clinical hyperpolarized [1-¹³C]pyruvate studies because of their speed, efficiency, and flexibility. In contrast, preclinical systems typically rely on slower spectroscopic methods, such as chemical shift imaging (CSI). In this study, a 2D spspEPI sequence was developed for use on a preclinical 3T Bruker system and tested on in vivo mice experiments with patient-derived xenograft renal cell carcinoma (RCC) or prostate cancer tissues implanted in the kidney or liver. Compared to spspEPI sequences, CSI were found to have a broader point spread function via simulations and exhibited signal bleeding between vasculature and tumors in vivo. Parameters for the spspEPI sequence were optimized using simulations and verified with in vivo data. The expected lactate SNR and pharmacokinetic modeling accuracy increased with lower pyruvate flip angles (less than 15°), intermediate lactate flip angles (25° to 40°), and temporal resolution of 3 s. Overall SNR was also higher with coarser spatial resolution (4 mm isotropic vs. 2 mm isotropic). Pharmacokinetic modelling used to fit k_PL maps showed results consistent with the previous literature and across different sequences and tumor xenografts. This work describes and justifies the pulse design and parameter choices for preclinical spspEPI hyperpolarized ¹³C-pyruvate studies and shows superior image quality to CSI.

Purpose

Rapid chemical exchange can affect SNR and pH measurement accuracy for hyperpolarized pH imaging with [¹³ C]bicarbonate. The purpose of this work was to investigate chemical exchange effects on hyperpolarized imaging sequences to identify optimal sequence parameters for high SNR and pH accuracy.

Methods

Simulations were performed under varying rates of bicarbonate-CO₂ chemical exchange to analyze exchange effects on pH quantification accuracy and SNR under different sampling schemes. Four pulse sequences, including 1 new technique, a multiple-excitation 2D EPI (multi-EPI) sequence, were compared in phantoms using hyperpolarized [¹³ C]bicarbonate, varying parameters such as tip angles, repetition time, order of metabolite excitation, and refocusing pulse design. In vivo hyperpolarized bicarbonate-CO₂ exchange measurements were made in transgenic murine prostate tumors to select in vivo imaging parameters.

Results

Modeling of bicarbonate-CO₂ exchange identified a multiple-excitation scheme for increasing CO₂ SNR by up to a factor of 2.7. When implemented in phantom imaging experiments, these sampling schemes were confirmed to yield high pH accuracy and SNR gains. Based on measured bicarbonate-CO₂ exchange in vivo, a 47% CO₂ SNR gain is predicted.

Conclusion

The novel multi-EPI pulse sequence can boost CO₂ imaging signal in hyperpolarized ¹³ C bicarbonate imaging while introducing minimal pH bias, helping to surmount a major hurdle in hyperpolarized pH imaging.

A robust and selective late-stage deuteration methodology was applied to 13C-enriched amino and alpha hydroxy acids to increase spin-lattice relaxation constant T1 for hyperpolarized 13C magnetic resonance imaging. For the five substrates with 13C-labeling on the C1-position ([1-13C]alanine, [1-13C]serine, [1-13C]lactate, [1-13C]glycine, and [1-13C]valine), significant increase of their T1 was observed at 3 T with deuterium labeling (+26%, 22%, +16%, +25% and +29%, respectively). Remarkably, in the case of [2-13C]alanine, [2-13C]serine and [2-13C]lactate, deuterium labeling led to a greater than four fold increase in T1. [1-13C,2-2H]alanine, produced using this method, was applied to in vitro enzyme assays with alanine aminotransferase, demonstrating a kinetic isotope effect.

N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), one of Good's buffers, was applied to pH imaging using hyperpolarized (13)C magnetic resonance spectroscopy. Rapid NMR- and MRI-based pH measurements were obtained by exploiting the sensitive pH-dependence of its (13)C chemical shift within the physiologic range.