The NMR hyperpolarization of uniformly 15 N-labeled [ 15 N 3 ]metronidazole is demonstrated by using SABRE-SHEATH. In this antibiotic, the 15 NO 2 group is hyperpolarized throughs pin relays createdb y 15 Ns pins in [ 15 N 3 ]metronidazole, and the polarization is transferred from parahydrogen-derivedh ydrides over six chemical bonds. In less than am inute of parahydrogen bubbling at approximately 0.4 mT, ah igh level of nuclear spin polarization( P 15N ) of around 16 %i sa chieved on all three 15 Ns ites. This prod-uct of 15 Np olarization andc oncentration of 15 Ns pins is arounds ix-fold bettert han any previous value determined for 15 NS ABRE-derived hyperpolarization. At 1.4 T, the hyperpolarized state persists fort ens of minutes (relaxation time, T 1 %10 min). An ovel synthesis of uniformly 15 N-enriched metronidazole is reported with ay ield of 15 %. This approachc an potentially be used for synthesis of aw ide variety of in vivom etabolic probesw ith potentialu ses ranging from hypoxiasensing to theranostic imaging.[a] Prof.
The presence of 14N nucleus in the scalar coupling network results in a 3-fold decrease of 15N T1 and polarization values for all 15N sites in 15N2-metronidazole versus15N3-metronidazole in SABRE hyperpolarization in microtesla fields.
Hyperpolarized forms of 1-13C-acetates and 1-13C-pyruvates are used as diagnostic
contrast agents for molecular
imaging of many diseases and disorders. Here, we report the synthetic
preparation of 1-13C isotopically enriched and pure from
solvent acetates and pyruvates derivatized with unsaturated ester
moiety. The reported unsaturated precursors can be employed for NMR
hyperpolarization of 1-13C-acetates and 1-13C-pyruvates via parahydrogen-induced polarization (PHIP). In this
PHIP variant, Side arm hydrogenation (SAH) of unsaturated ester moiety
is followed by the polarization transfer from nascent parahydrogen
protons to 13C nucleus via magnetic field cycling procedure
to achieve hyperpolarization of 13C nuclear spins. This
work reports the synthesis of PHIP-SAH precursors: vinyl 1-13C-acetate (55% yield), allyl 1-13C-acetate (70% yield),
propargyl 1-13C-acetate (45% yield), allyl 1-13C-pyruvate (60% yield), and propargyl 1-13C-pyruvate (35%
yield). Feasibility of PHIP-SAH 13C hyperpolarization was
verified by 13C NMR spectroscopy: hyperpolarized allyl
1-13C-pyruvate was produced from propargyl 1-13C-pyruvate with 13C polarization of ∼3.2% in CD3OD and ∼0.7% in D2O. 13C magnetic
resonance imaging is demonstrated with hyperpolarized 1-13C-pyruvate in aqueous medium.
Nimorazole belongs to the imidazole‐based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [15N3]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next‐generation MRI‐LINAC systems. Herein, we report the first steps to create long‐lasting (for tens of minutes) hyperpolarized state on three 15N sites of [15N3]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding to P15N of 3.2 %) by 15N−15N spin‐relayed SABRE‐SHEATH hyperpolarization technique, relying on simultaneous exchange of [15N3]nimorazole and parahydrogen on polarization transfer Ir‐IMes catalyst. The presented results pave the way to efficient spin‐relayed SABRE‐SHEATH hyperpolarization of a wide range of imidazole‐based antibiotics and chemotherapeutics.
Signal Amplification By Reversible Exchange (SABRE) is a new and rapidly developing hyperpolarization technique. The recent discovery of Spin-Lock Induced Crossing SABRE (SLIC-SABRE) shows that high field hyperpolarization transfer techniques developed so far were optimized for singlet spin order that does not coincide with the experimentally produced spin state. Here, we investigate the SLIC-SABRE approach and the most advanced quantitative theoretical SABRE model. It is the goal to achieve the highest possible polarization with SLIC-SABRE at high field using the standard SABRE system, IrIMes catalyst with pyridine. We demonstrate the accuracy of SABRE model describing the effects of various physical parameters such as the amplitude and frequency of the radio-frequency field, and the effects of chemical parameters such as the exchange rate constants. The combined use of experiments and theory allows to determine the effective lifetime of SABRE-complex. Furthermore, the entropy and enthalpy of the SABRE-complex dissociation reaction based on the temperature dependence of SLIC-SABRE signal can be accessed. We show, for the first time, that this SLIC-SABRE model can be useful for the evaluation of the chemical exchange parameters that are very important for the production of highly polarized contrast agents via SABRE.
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