Efficient SABRE-SHEATH Hyperpolarization of Potent Branched-Chain-Amino-Acid Metabolic Probe [1-13C]ketoisocaproate
| Autor: | Md Raduanul Chowdhury, Shiraz Nantogma, Luke Stilgenbauer, Firoz Ahmed, Boyd Goodson, Clementinah Oladun, Marianna Sadagurski, Thomas Theis, Eduard Chekmenev, Isaiah Adelabu |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Zdroj: | Metabolites Volume 13 Issue 2 Pages: 200 |
| ISSN: | 2218-1989 |
| DOI: | 10.3390/metabo13020200 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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