Simultaneous imaging of hyperpolarized [1,4‐¹³C₂]fumarate, [1‐¹³C]pyruvate and ¹⁸F–FDG in a rat model of necrosis in a clinical PET/MR scanner

Abstract

A co-polarization scheme for [1,4- C ]fumarate and [1- C]pyruvate is presented to simultaneously assess necrosis and metabolism in rats with hyperpolarized C magnetic resonance (MR). The co-polarization was performed in a SPINlab polarizer. In addition, the feasibility of simultaneous positron emission tomography (PET) and MR of small animals with a clinical PET/MR scanner is demonstrated. The hyperpolarized metabolic MR and PET was demonstrated in a rat model of necrosis. The polarization and T of the co-polarized [1,4- C ]fumarate and [1- C]pyruvate substrates were measured in vitro and compared with those obtained when the substrates were polarized individually. A polarization of 36 ± 4% for fumarate and 37 ± 6% for pyruvate was obtained. We found no significant difference in the polarization and T values between the dual and single substrate polarization. Rats weighing about 400 g were injected intramuscularly in one of the hind legs with 200 μL of turpentine to induce necrosis. Two hours later, C metabolic maps were obtained with a chemical shift imaging sequence (16 × 16) with a resolution of 3.1 × 5.0 × 25.0 mm . The C spectroscopic images were acquired in 12 s, followed by an 8-min F-2-fluoro-2-deoxy-d-glucose ( F-FDG) PET acquisition with a resolution of 3.5 mm. [1,4- C ]Malate was observed from the tissue injected with turpentine indicating necrosis. Normal [1- C]pyruvate metabolism and F-FDG uptake were observed from the same tissue. The proposed co-polarization scheme provides a means to utilize multiple imaging agents simultaneously, and thus to probe various metabolic pathways in a single examination. Moreover, it demonstrates the feasibility of small animal research on a clinical PET/MR scanner for combined PET and hyperpolarized metabolic MR.

Biomedical Applications of the Dynamic Nuclear Polarization and Parahydrogen Induced Polarization Techniques for Hyperpolarized ¹³C MR Imaging

“…5a) in breast cancer 106 and efficient co-polarization schemes offer simultaneous probing of multiple metabolic pathways. 107 Hyperpolarization of the reduced and oxidized forms of vitamin C-namely [1-13 C]dehydroascorbate and [1-13 C] ascorbate, respectively-offers a novel means to probe intracellular redox status, a critical factor in normal and abnormal cellular function. 108,109 High concentrations of [1-13 C]ascorbate can be observed post-injection of [1-13 C]dehydroascorbate, and reduced HP [1-13 C]ascorbate signal has been utilized as an MR biomarker of renal oxidative stress.…”

Dynamic metabolic imaging of copolarized [2‐13C]pyruvate and [1,4‐13C2]fumarate using 3D‐spiral CSI with alternate spectral band excitation

“…The [2‐ 13 C]Pyr (14 M) sample is prepared by mixing AH111501 trityl radical (GE Healthcare, Oslo, Norway) in [2‐ 13 C]Pyruvic acid (Sigma Aldrich, St Louis, MO), whereas the [1,4‐ 13 C 2 ]Fum (3.5 M) sample was prepared by dissolving [1,4‐ 13 C 2 ]Fumaric acid (Cambridge Isotope Laboratories, Cambridge, MA) crystals in dimethyl sulfoxide (DMSO) (Sigma Aldrich, USA) followed by the addition of AH111501 trityl radical. The copolarized mixture consists of 50 µL of [2‐ 13 C]Pyr and 100 µL of [1,4‐ 13 C 2 ]Fum and the copolarization was done using a SPINlab Hyperpolarizer (Research Circle Technology) operating at 5.0T and 0.82 K. Following the procedure described by Eldirdiri et al, the sample mixture was prepared by first adding the measured [2‐ 13 C]Pyr to the sample vial and freezing it.…”

“…The RF pulses and transmitter frequency are shifted alternately during each subsequent sampling interval to acquire both sub-bands during same experiment. ]Fum and the copolarization was done using a SPINlab Hyperpolarizer (Research Circle Technology) operating at 5.0T and 0.82 K. Following the procedure described by Eldirdiri et al, 19 the sample mixture was prepared by first adding the measured [2-13 C]Pyr to the sample vial and freezing it.…”

“…Additionally, conversion of hyperpolarized 13 C‐labeled fumarate (Fum) to malate (Mal) has been proposed as a biomarker for cell necrosis . Metabolic imaging of hyperpolarized 13 C‐labeled Pyr and Fum has shown great potential in characterizing multiple diseases and assessing response to treatment with Pyr already translated into the clinic . Thus, performing their measurements with a single injection of copolarized substrates would be advantageous particularly for the clinical translation of this technology.…”

Emerging Technologies to Image Tissue Metabolism

“…Early studies showed that it could be used to provide early evidence of tumor cell death after treatment (Gallagher et al, 2009;Witney et al, 2010) and that it was more effective at detecting low levels of diffuse necrosis than diffusion-weighted 1 H MRI (Bohndiek et al, 2010). The technique can also be used to detect cell death in other tissues, such as kidney (Clatworthy et al, 2012) and muscle (Eldirdiri et al, 2017). In a recent study, hyperpolarized [1-13 C]pyruvate, [ 13 C]urea and [1,4-13 C 2 ]fumarate were used to assess the effects of transcatheter arterial embolization in an orthotopic rat hepatocellular carcinoma model.…”