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

Isaiah Adelabu; Md Raduanul H. Chowdhury; Shiraz Nantogma; Clementinah Oladun; Firoz Ahmed; Lukas Stilgenbauer; Marianna Sadagurski; Thomas Theis; Boyd M. Goodson; Eduard Y. Chekmenev

doi:10.3390/metabo13020200

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

Shiraz Nantogma·Isaiah Adelabu·Md Raduanul H. Chowdhury·Shiraz Nantogma·Clementinah Oladun·Firoz Ahmed·Lukas Stilgenbauer·Marianna Sadagurski·Thomas Theis·Boyd M. Goodson·Eduard Y. Chekmenev

MetabolitesVol. 13Issue 2January 29, 2023DOI: 10.3390/metabo13020200

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Abstract

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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Adelabu, I., Chowdhury, M., Nantogma, S., Oladun, C., Ahmed, F., Stilgenbauer, L., Sadagurski, M., Theis, T., Goodson, B., & Chekmenev, E. (2023). Efficient SABRE-SHEATH Hyperpolarization of Potent Branched-Chain-Amino-Acid Metabolic Probe [1-13C]ketoisocaproate. Metabolites, 13(2). https://doi.org/10.3390/metabo13020200

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

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