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1. PHIP hyperpolarized [1-13C]pyruvate and [1-13C]acetate esters via PH-INEPT polarization transfer monitored by 13C NMR and MRI

   https://doi.org/10.1038/s41598-021-85136-2  

   Svyatova, Alexandra; Kozinenko, Vitaly P.; Chukanov, Nikita V.; Burueva, Dudari B.; Chekmenev, Eduard Y.; Chen, Yu-Wen; Hwang, Dennis W.; Kovtunov, Kirill V.; Koptyug, Igor V. (December 2021, Scientific Reports)

   null (Ed.)

   Abstract Parahydrogen-induced polarization of 13 C nuclei by side-arm hydrogenation (PHIP-SAH) for [1- 13 C]acetate and [1- 13 C]pyruvate esters with application of PH-INEPT-type pulse sequences for 1 H to 13 C polarization transfer is reported, and its efficiency is compared with that of polarization transfer based on magnetic field cycling (MFC). The pulse-sequence transfer approach may have its merits in some applications because the entire hyperpolarization procedure is implemented directly in an NMR or MRI instrument, whereas MFC requires a controlled field variation at low magnetic fields. Optimization of the PH-INEPT-type transfer sequences resulted in 13 C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for 1 H to 13 C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1- 13 C]pyruvate and ethyl [1- 13 C]acetate, respectively). Nevertheless, a significant 13 C NMR signal enhancement with respect to thermal polarization allowed us to perform 13 C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications. 

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2. High field para hydrogen induced polarization of succinate and phospholactate

   https://doi.org/10.1039/d0cp06281b  

   Berner, Stephan; Schmidt, Andreas B.; Ellermann, Frowin; Korchak, Sergey; Chekmenev, Eduard Y.; Glöggler, Stefan; von Elverfeldt, Dominik; Hennig, Jürgen; Hövener, Jan-Bernd (January 2021, Physical Chemistry Chemical Physics)

   null (Ed.)

   The signal enhancement provided by the hyperpolarization of nuclear spins of metabolites is a promising technique for diagnostic magnetic resonance imaging (MRI). To date, most 13 C-contrast agents are hyperpolarized utilizing a complex or cost-intensive polarizer. Recently, the in situ para hydrogen-induced 13 C hyperpolarization was demonstrated. Hydrogenation, spin order transfer (SOT) by a pulsed NMR sequence, in vivo administration, and detection was achieved within the magnet bore of a 7 Tesla MRI system. So far, the hyperpolarization of the xenobiotic molecule 1- 13 C-hydroxyethylpropionate (HEP) and the biomolecule 1- 13 C-succinate (SUC) through the PH-INEPT+ sequence and a SOT scheme proposed by Goldman et al. , respectively, was shown. Here, we investigate further the hyperpolarization of SUC at 7 Tesla and study the performance of two additional SOT sequences. Moreover, we present first results of the hyperpolarization at high magnetic field of 1- 13 C-phospholactate (PLAC), a derivate to obtain the metabolite lactate, employing the PH-INEPT+ sequence. For SUC and PLAC, 13 C polarizations of about 1–2% were achieved within seconds and with minimal equipment. Effects that potentially may explain loss of 13 C polarization have been identified, i.e. low hydrogenation yield, fast T 1 / T 2 relaxation and the rarely considered 13 C isotope labeling effect. 

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3. In vivo Metabolic Sensing of Hyperpolarized [1‐ ¹³ C]Pyruvate in Mice Using a Recyclable Perfluorinated Iridium Signal Amplification by Reversible Exchange Catalyst

   https://doi.org/10.1002/anie.202407349  

   Ettedgui, Jessica; Yamamoto, Kazutoshi; Blackman, Burchelle; Koyasu, Norikazu; Raju, Natarajan; Vasalatiy, Olga; Merkle, Hellmut; Chekmenev, Eduard Y; Goodson, Boyd M; Krishna, Murali C; et al (July 2024, Angewandte Chemie International Edition)

   Abstract Real‐time visualization of metabolic processes in vivo provides crucial insights into conditions like cancer and metabolic disorders. Metabolic magnetic resonance imaging (MRI), by amplifying the signal of pyruvate molecules through hyperpolarization, enables non‐invasive monitoring of metabolic fluxes, aiding in understanding disease progression and treatment response. Signal Amplification By Reversible Exchange (SABRE) presents a simpler, cost‐effective alternative to dissolution dynamic nuclear polarization, eliminating the need for expensive equipment and complex procedures. We present the first in vivo demonstration of metabolic sensing in a human pancreatic cancer xenograft model compared to healthy mice. A novel perfluorinated Iridium SABRE catalyst in a fluorinated solvent and methanol blend facilitated this breakthrough with a 1.2‐fold increase in [1‐¹³C]pyruvate SABRE hyperpolarization. The perfluorinated moiety allowed easy separation of the heavy‐metal‐containing catalyst from the hyperpolarized [1‐¹³C]pyruvate target. The perfluorinated catalyst exhibited recyclability, maintaining SABRE‐SHEATH activity through subsequent hyperpolarization cycles with minimal activity loss after the initial two cycles. Remarkably, the catalyst retained activity for at least 10 cycles, with a 3.3‐fold decrease in hyperpolarization potency. This proof‐of‐concept study encourages wider adoption of SABRE hyperpolarized [1‐¹³C]pyruvate MR for studying in vivo metabolism, aiding in diagnosing stages and monitoring treatment responses in cancer and other diseases. 

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4. In Vivo Metabolic Imaging of [1‐ ¹³ C]Pyruvate‐d ₃ Hyperpolarized By Reversible Exchange With Parahydrogen**

   https://doi.org/10.1002/anie.202306654  

   de_Maissin, Henri; Groß, Philipp R; Mohiuddin, Obaid; Weigt, Moritz; Nagel, Luca; Herzog, Marvin; Wang, Zirun; Willing, Robert; Reichardt, Wilfried; Pichotka, Martin; et al (September 2023, Angewandte Chemie International Edition)

   Abstract Metabolic magnetic resonance imaging (MRI) using hyperpolarized (HP) pyruvate is becoming a non‐invasive technique for diagnosing, staging, and monitoring response to treatment in cancer and other diseases. The clinically established method for producing HP pyruvate, dissolution dynamic nuclear polarization, however, is rather complex and slow. Signal Amplification By Reversible Exchange (SABRE) is an ultra‐fast and low‐cost method based on fast chemical exchange. Here, for the first time, we demonstrate not only in vivo utility, but also metabolic MRI with SABRE. We present a novel routine to produce aqueous HP [1‐¹³C]pyruvate‐d₃for injection in 6 minutes. The injected solution was sterile, non‐toxic, pH neutral and contained ≈30 mM [1‐¹³C]pyruvate‐d₃polarized to ≈11 % (residual 250 mM methanol and 20 μM catalyst). It was obtained by rapid solvent evaporation and metal filtering, which we detail in this manuscript. This achievement makes HP pyruvate MRI available to a wide biomedical community for fast metabolic imaging of living organisms. 

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5. Efficient SABRE-SHEATH Hyperpolarization of Potent Branched-Chain-Amino-Acid Metabolic Probe [1-13C]ketoisocaproate

   https://doi.org/10.3390/metabo13020200  

   Adelabu, Isaiah; Chowdhury, Md Raduanul; Nantogma, Shiraz; Oladun, Clementinah; Ahmed, Firoz; Stilgenbauer, Lukas; Sadagurski, Marianna; Theis, Thomas; Goodson, Boyd M.; Chekmenev, Eduard Y. (February 2023, Metabolites)

   Efficient 13C hyperpolarization of ketoisocaproate is demonstrated in natural isotopic abundance and [1-13C]enriched forms via SABRE-SHEATH (Signal Amplification By Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei). Parahydrogen, as the source of nuclear spin order, and ketoisocaproate undergo simultaneous chemical exchange with an Ir-IMes-based hexacoordinate complex in CD3OD. SABRE-SHEATH enables spontaneous polarization transfer from parahydrogen-derived hydrides to the 13C nucleus of transiently bound ketoisocaproate. 13C polarization values of up to 18% are achieved at the 1-13C site in 1 min in the liquid state at 30 mM substrate concentration. The efficient polarization build-up becomes possible due to favorable relaxation dynamics. Specifically, the exponential build-up time constant (14.3 ± 0.6 s) is substantially lower than the corresponding polarization decay time constant (22.8 ± 1.2 s) at the optimum polarization transfer field (0.4 microtesla) and temperature (10 °C). The experiments with natural abundance ketoisocaproate revealed polarization level on the 13C-2 site of less than 1%—i.e., one order of magnitude lower than that of the 1-13C site—which is only partially due to more-efficient relaxation dynamics in sub-microtesla fields. We rationalize the overall much lower 13C-2 polarization efficiency in part by less favorable catalyst-binding dynamics of the C-2 site. Pilot SABRE experiments at pH 4.0 (acidified sample) versus pH 6.1 (unaltered sodium [1-13C]ketoisocaproate) reveal substantial modulation of SABRE-SHEATH processes by pH, warranting future systematic pH titration studies of ketoisocaproate, as well as other structurally similar ketocarboxylate motifs including pyruvate and alpha-ketoglutarate, with the overarching goal of maximizing 13C polarization levels in these potent molecular probes. Finally, we also report on the pilot post-mortem use of HP [1-13C]ketoisocaproate in a euthanized mouse, demonstrating that SABRE-hyperpolarized 13C contrast agents hold promise for future metabolic studies. 

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