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Rapid 13C Hyperpolarization of the TCA Cycle Intermediate α-Ketoglutarate via SABRE-SHEATH
Analytical Chemistry ( IF 6.7 ) Pub Date : 2022-09-22 , DOI: 10.1021/acs.analchem.2c02160 Isaiah Adelabu 1 , Jessica Ettedgui 2 , Sameer M Joshi 1 , Shiraz Nantogma 1 , Md Raduanul H Chowdhury 1 , Stephen McBride 3 , Thomas Theis 3 , Venkata R Sabbasani 2 , Mushti Chandrasekhar 2 , Deepak Sail 2 , Kazutoshi Yamamoto 4 , Rolf E Swenson 2 , Murali C Krishna 5 , Boyd M Goodson 6 , Eduard Y Chekmenev 1
Analytical Chemistry ( IF 6.7 ) Pub Date : 2022-09-22 , DOI: 10.1021/acs.analchem.2c02160 Isaiah Adelabu 1 , Jessica Ettedgui 2 , Sameer M Joshi 1 , Shiraz Nantogma 1 , Md Raduanul H Chowdhury 1 , Stephen McBride 3 , Thomas Theis 3 , Venkata R Sabbasani 2 , Mushti Chandrasekhar 2 , Deepak Sail 2 , Kazutoshi Yamamoto 4 , Rolf E Swenson 2 , Murali C Krishna 5 , Boyd M Goodson 6 , Eduard Y Chekmenev 1
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α-Ketoglutarate is a key biomolecule involved in a number of metabolic pathways─most notably the TCA cycle. Abnormal α-ketoglutarate metabolism has also been linked with cancer. Here, isotopic labeling was employed to synthesize [1-13C,5-12C,D4]α-ketoglutarate with the future goal of utilizing its [1-13C]-hyperpolarized state for real-time metabolic imaging of α-ketoglutarate analytes and its downstream metabolites in vivo. The signal amplification by reversible exchange in shield enables alignment transfer to heteronuclei (SABRE-SHEATH) hyperpolarization technique was used to create 9.7% [1-13C] polarization in 1 minute in this isotopologue. The efficient 13C hyperpolarization, which utilizes parahydrogen as the source of nuclear spin order, is also supported by favorable relaxation dynamics at 0.4 μT field (the optimal polarization transfer field): the exponential 13C polarization buildup constant Tb is 11.0 ± 0.4 s whereas the 13C polarization decay constant T1 is 18.5 ± 0.7 s. An even higher 13C polarization value of 17.3% was achieved using natural-abundance α-ketoglutarate disodium salt, with overall similar relaxation dynamics at 0.4 μT field, indicating that substrate deuteration leads only to a slight increase (∼1.2-fold) in the relaxation rates for 13C nuclei separated by three chemical bonds. Instead, the gain in polarization (natural abundance versus [1-13C]-labeled) is rationalized through the smaller heat capacity of the “spin bath” comprising available 13C spins that must be hyperpolarized by the same number of parahydrogen present in each sample, in line with previous 15N SABRE-SHEATH studies. Remarkably, the C-2 carbon was not hyperpolarized in both α-ketoglutarate isotopologues studied; this observation is in sharp contrast with previously reported SABRE-SHEATH pyruvate studies, indicating that the catalyst-binding dynamics of C-2 in α-ketoglutarate differ from that in pyruvate. We also demonstrate that 13C spectroscopic characterization of α-ketoglutarate and pyruvate analytes can be performed at natural 13C abundance with an estimated detection limit of 80 micromolar concentration × *%P13C. All in all, the fundamental studies reported here enable a wide range of research communities with a new hyperpolarized contrast agent potentially useful for metabolic imaging of brain function, cancer, and other metabolically challenging diseases.
中文翻译：
通过 SABRE-SHEATH TCA 循环中间体 α-酮戊二酸的快速 13C 超极化
α-酮戊二酸是参与多种代谢途径（尤其是 TCA 循环）的关键生物分子。α-酮戊二酸代谢异常也与癌症有关。在这里，采用同位素标记来合成[1- 13 C,5- 12 C,D 4 ]α-酮戊二酸，未来的目标是利用其[1- 13 C]-超极化状态进行α-的实时代谢成像体内酮戊二酸分析物及其下游代谢物。通过屏蔽中的可逆交换进行信号放大，使对准转移到异核 (SABRE-SHEATH) 超极化技术用于在该同位素体中在 1 分钟内产生 9.7% [1- 13 C] 极化。利用仲氢作为核自旋序源的有效13 C 超极化也得到了 0.4 μT 场（最佳极化转移场）的有利弛豫动力学的支持：指数 13 C 极化建立常数 T b为11.0 ± 0.4 s而13 C极化衰减常数T 1为18.5±0.7s。使用天然丰度的 α-酮戊二酸二钠盐实现了 17.3% 的更高13 C 极化值，在 0.4 μT 场下具有总体相似的弛豫动力学，表明底物氘化仅导致由三个化学键分隔的13 C 原子核的弛豫率。相反，极化增益（自然丰度与 [1- 13 C] 标记）通过“旋转浴”的较小热容合理化，该“旋转浴”包含可用的13 C 自旋，必须通过每个中存在的相同数量的仲氢进行超极化。样本，与之前的15 N SABRE-SHEATH 研究一致。值得注意的是，在所研究的两种 α-酮戊二酸同位素异数体中，C-2 碳并未超极化。这一观察结果与之前报道的 SABRE-SHEATH 丙酮酸研究形成鲜明对比，表明 α-酮戊二酸中 C-2 的催化剂结合动力学不同于丙酮酸中的催化剂结合动力学。我们还证明，α-酮戊二酸和丙酮酸分析物的13 C 光谱表征可以在天然13 C 丰度下进行，估计检测限为 80 微摩尔浓度 × *% P 13C。总而言之，这里报告的基础研究使广泛的研究团体能够使用一种新的超极化造影剂，该造影剂可能可用于脑功能、癌症和其他代谢挑战性疾病的代谢成像。
更新日期：2022-09-22
中文翻译：
通过 SABRE-SHEATH TCA 循环中间体 α-酮戊二酸的快速 13C 超极化
α-酮戊二酸是参与多种代谢途径（尤其是 TCA 循环）的关键生物分子。α-酮戊二酸代谢异常也与癌症有关。在这里，采用同位素标记来合成[1- 13 C,5- 12 C,D 4 ]α-酮戊二酸，未来的目标是利用其[1- 13 C]-超极化状态进行α-的实时代谢成像体内酮戊二酸分析物及其下游代谢物。通过屏蔽中的可逆交换进行信号放大，使对准转移到异核 (SABRE-SHEATH) 超极化技术用于在该同位素体中在 1 分钟内产生 9.7% [1- 13 C] 极化。利用仲氢作为核自旋序源的有效13 C 超极化也得到了 0.4 μT 场（最佳极化转移场）的有利弛豫动力学的支持：指数 13 C 极化建立常数 T b为11.0 ± 0.4 s而13 C极化衰减常数T 1为18.5±0.7s。使用天然丰度的 α-酮戊二酸二钠盐实现了 17.3% 的更高13 C 极化值，在 0.4 μT 场下具有总体相似的弛豫动力学，表明底物氘化仅导致由三个化学键分隔的13 C 原子核的弛豫率。相反，极化增益（自然丰度与 [1- 13 C] 标记）通过“旋转浴”的较小热容合理化，该“旋转浴”包含可用的13 C 自旋，必须通过每个中存在的相同数量的仲氢进行超极化。样本，与之前的15 N SABRE-SHEATH 研究一致。值得注意的是，在所研究的两种 α-酮戊二酸同位素异数体中，C-2 碳并未超极化。这一观察结果与之前报道的 SABRE-SHEATH 丙酮酸研究形成鲜明对比，表明 α-酮戊二酸中 C-2 的催化剂结合动力学不同于丙酮酸中的催化剂结合动力学。我们还证明，α-酮戊二酸和丙酮酸分析物的13 C 光谱表征可以在天然13 C 丰度下进行，估计检测限为 80 微摩尔浓度 × *% P 13C。总而言之，这里报告的基础研究使广泛的研究团体能够使用一种新的超极化造影剂，该造影剂可能可用于脑功能、癌症和其他代谢挑战性疾病的代谢成像。
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