We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-13C-phosphoenolpyruvate and 1-13C-phosphoenolpyruvate-d2 for application in hyperpolarized imaging technology. 1-13C-Phosphoenolpyruvate-d2 was synthesized with 57% overall yield (over two steps), and >98% 2H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-13C-phosphoenolpyruvate. These two unsaturated compounds with C=C bonds were employed for parahydrogen-induced polarization via pairwise parahydrogen addition in aqueous medium. We find that deuteration of 1-13C-phosphoenolpyruvate resulted in overall increase of 1H T1 of nascent hyperpolarized protons (4.30 ± 0.04 s versus 2.06 ± 0.01 s) and 1H polarization (∼2.5% versus ∼0.7%) of the resulting hyperpolarized 1-13C-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1-13C nucleus via a magnetic field cycling procedure. The proton T1 increase in deuterated hyperpolarized 1-13C-phospholactate yielded approximately 30% better 13C polarization compared to that of nondeuterated hyperpolarized 1-13C-phospholactate. Analysis of T1 relaxation revealed that deuteration of 1-13C-phospholactate may have resulted in approximately 3-fold worse 1H → 13C polarization transfer efficiency via magnetic field cycling. Since magnetic field cycling is a key polarization transfer step in the side-arm hydrogenation approach, the presented findings may guide more rational design of a broad range of 13C hyperpolarized contrast agents for molecular imaging employing 13C MRI. The hyperpolarized 1-13C-phospholactate-d2 is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes 13C hyperpolarized lactate, which as we show can be detected in the brain by 13C hyperpolarized MRI; this feasibility demonstration has implications for future imaging of neurodegenerative diseases and dementia.
- C-13 POLARIZATION
- HYDROGEN-INDUCED POLARIZATION
- HYPERPOLARIZED CONTRAST AGENTS
- PASADENA HYPERPOLARIZATION
- SPIN ORDER