Effects of Deuteration of C-13-Enriched Phospholactate on Efficiency of Parahydrogen-Induced Polarization by Magnetic Field Cycling

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-C-13-phosphoenolpyruvate and 1-C-13-phosphoenolpyruvate-d(2) for application in hyperpolarized imaging technology. 1-C-13-Phosphoenolpyruvate-d(2) was synthesized with 57% overall yield (over two steps), and >98% H-2 isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-C-13-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-C-13-phosphoenolpyruvate resulted in overall increase of H-1 T-1 of nascent hyperpolarized protons (4.30 +/- 0.04 s versus 2.06 +/- 0.01 s) and H-1 polarization (similar to 2.5% versus similar to 0.7%) of the resulting hyperpolarized 1-C-13-phospholactate. The nuclear spin polarization of nascent parahydrogen-derived protons was transferred to 1-C-13 nucleus via a magnetic field cycling procedure. The proton T-1 increase in deuterated hyperpolarized 1-C-13-phospholactate yielded approximately 30% better C-13 polarization compared to that of nondeuterated hyperpolarized 1-C-13-phospholactate. Analysis of T-1 relaxation revealed that deuteration of 1-C-13-phospholactate may have resulted in approximately 3-fold worse H-1 -> C-13 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 C-13 hyperpolarized contrast agents for molecular imaging employing C-13 MRI. The hyperpolarized 1-C-13-phospholactate-d(2) is of biomedical imaging relevance because it undergoes in vivo dephosphorylation and becomes C-13 hyperpolarized lactate, which as we show can be detected in the brain by C-13 hyperpolarized MR1; this feasibility demonstration has implications for future imaging of neurodegenerative diseases and dementia.