Spin-Lattice Relaxation of Hyperpolarized Metronidazole in Signal Amplification by Reversible Exchange in Micro-Tesla Fields.

Simultaneous reversible chemical exchange of parahydrogen and to-be-hyperpolarized substrate on metal centers enables spontaneous transfer of spin order from parahydrogen singlet to nuclear spins of the substrate. When performed at sub-micro-Tesla magnetic field, this technique of NMR Signal Amplification by Reversible Exchange in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH). SABRE-SHEATH has been shown to hyperpolarize nitrogen-15 sites of a wide range of biologically interesting molecules to a high polarization level (P > 20%) in one minute. Here, we report on a systematic study of 1H, 13C and 15N spin-lattice relaxation (T1) of metronidazole-13C2-15N2 in SABRE-SHEATH hyperpolarization process. In micro-Tesla range, we find that all 1H, 13C and 15N spins studied share approximately the same T1 values (ca. 4 s at the conditions studied) due to mixing of their Zeeman levels, which is consistent with the model of relayed SABRE-SHEATH effect. These T1 values are significantly lower than those at higher magnetic (i.e. the Earth's magnetic field and above), which exceed 3 minutes in some cases. Moreover, these relatively short T1 values observed below 1 micro-Tesla limit the polarization build-up process of SABRE-SHEATH- thereby, limiting maximum attainable 15N polarization. The relatively short nature of T1 values observed below 1 micro-Tesla is primarily caused by intermolecular interactions with quadrupolar iridium centers or dihydride protons of the employed polarization transfer catalyst, whereas intramolecular spin-spin interactions with 14N quadrupolar centers have significantly smaller contribution. The presented experimental results and their analysis will be beneficial for more rational design of SABRE-SHEATH (i) polarization transfer catalyst, and (ii) hyperpolarized molecular probes in the context of biomedical imaging and other applications.

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

We report herein a large-scale (>10 g) synthesis of isotopically enriched 1-13C-phosphoenolpyruvate and 1-13C-phosphoenolpyruvate-d2 for application in hyperpolarized imaging technology. The 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 magnetic field cycling procedure. The proton T1 increase in hyperpolarized deuterated 1-13C-phospholactate yielded approximately 30% better 13C polarization compared to non-deuterated hyperpolarized 1-13C-phospholactate. Analysis of T1 relaxation revealed that deuteration of 1-13C-phospholactate may have resulted in approximately 3-fold worse H→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 rationale design of contrast agents using parahydrogen polarization 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 using 13C hyperpolarized MRI; an implication for future imaging of neurodegenerative diseases and dementia.

Spin Relays Enable Efficient Long-Range Heteronuclear Signal Amplification By Reversible Exchange.

A systematic experimental study is reported on the polarization transfer to distant spins, which do not directly bind to the polarization transfer complexes employed in Signal Amplification By Reversible Exchange (SABRE) experiments. Both, long-range transfer to protons and long-range transfer to heteronuclei i.e. 13C and 15N are examined. Selective destruction of hyperpolarization on 1H, 13C, and 15N sites is employed, followed by their re-hyperpolarization from neighboring spins within the molecules of interest (pyridine for 1H studies and metronidazole-15N2-13C2 for 13C and 15N studies). We conclude that long-range sites can be efficiently hyperpolarized when a network of spin-½ nuclei enables relayed polarization transfer (i.e. via short-range interactions between sites). In case of proton SABRE in the milli-Tesla regime, a relay network consisting of protons only is sufficient. However, in case 13C and 15N are targeted (i.e. via SABRE in SHield Enables Alignment Transfer to Heteronuclei or SABRE-SHEATH experiment), the presence of a heteronuclear network (e.g. consisting of 15N) enables a relay mechanism that is significantly more efficient than the direct transfer of spin order from para-H2-derived hydrides.