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Parahydrogen-induced polarization of¹³C nuclei by side-arm hydrogenation (PHIP-SAH) for [1-¹³C]acetate and [1-¹³C]pyruvate esters with application of PH-INEPT-type pulse sequences for¹H to¹³C polarization transfer is reported, and its efficiency is compared with that of polarization transfer based on magnetic field cycling (MFC). The pulse-sequence transfer approach may have its merits in some applications because the entire hyperpolarization procedure is implemented directly in an NMR or MRI instrument, whereas MFC requires a controlled field variation at low magnetic fields. Optimization of the PH-INEPT-type transfer sequences resulted in¹³C polarization values of 0.66 ± 0.04% and 0.19 ± 0.02% for allyl [1-¹³C]pyruvate and ethyl [1-¹³C]acetate, respectively, which is lower than the corresponding polarization levels obtained with MFC for¹H to¹³C polarization transfer (3.95 ± 0.05% and 0.65 ± 0.05% for allyl [1-¹³C]pyruvate and ethyl [1-¹³C]acetate, respectively). Nevertheless, a significant¹³C NMR signal enhancement with respect to thermal polarization allowed us to perform¹³C MR imaging of both biologically relevant hyperpolarized molecules which can be used to produce useful contrast agents for the in vivo imaging applications.

 

15 N spin–lattice relaxation dynamics in metronidazole- 15 N 3 and metronidazole- 15 N 2 isotopologues are studied for rational design of 15 N-enriched biomolecules for signal amplification by reversible exchange in microtesla fields. 15 N relaxation dynamics mapping reveals the deleterious effects of interactions with the polarization transfer catalyst and a quadrupolar 14 N nucleus within the spin-relayed 15 N– 15 N network. 

Signal Amplification by Reversible Exchange (SABRE) technique enables nuclear spin hyperpolarization of wide range of compounds using parahydrogen. Here we present the synthetic approach to prepare¹⁵N‐labeled [¹⁵N]dalfampridine (4‐amino[¹⁵N]pyridine) utilized as a drug to reduce the symptoms of multiple sclerosis. The synthesized compound was hyperpolarized using SABRE at microtesla magnetic fields (SABRE‐SHEATH technique) with up to 2.0 %¹⁵N polarization. The 7‐hour‐long activation of SABRE pre‐catalyst [Ir(IMes)(COD)Cl] in the presence of [¹⁵N]dalfampridine can be remedied by the use of pyridine co‐ligand for catalyst activation while retaining the¹⁵N polarization levels of [¹⁵N]dalfampridine. The effects of experimental conditions such as polarization transfer magnetic field, temperature, concentration, parahydrogen flow rate and pressure on¹⁵N polarization levels of free and equatorial catalyst‐bound [¹⁵N]dalfampridine were investigated. Moreover, we studied¹⁵N polarization build‐up and decay at magnetic field of less than 0.04 μT as well as¹⁵N polarization decay at the Earth's magnetic field and at 1.4 T.

 

Magnetic resonance imaging of [1‐¹³C]hyperpolarized carboxylates (most notably, [1‐¹³C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of¹H and¹³C hyperpolarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties using heterogeneous hydrogenation of corresponding vinyl, allyl and propargyl precursors in isotopically unlabeled and 1‐¹³C‐enriched forms with parahydrogen over Rh/TiO₂catalysts in methanol‐d₄and in D₂O. The maximum obtained¹H polarization was 0.6±0.2 % (for propyl acetate in CD₃OD), while the highest¹³C polarization was 0.10±0.03 % (for ethyl acetate in CD₃OD). Hyperpolarization of acetate esters surpassed that of pyruvates, while esters with a triple carbon‐carbon bond in unsaturated alcoholic moiety were less efficient as parahydrogen‐induced polarization precursors than esters with a double bond. Among the compounds studied, the maximum¹H and¹³C NMR signal intensities were observed for propyl acetate. Ethyl acetate yielded slightly less intense NMR signals which were dramatically greater than those of other esters under study.

 

NMR hyperpolarization techniques enhance nuclear spin polarization by several orders of magnitude resulting in corresponding sensitivity gains. This enormous sensitivity gain enables new applications ranging from studies of small molecules by using high‐resolution NMR spectroscopy to real‐time metabolic imagingin vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the¹³C and¹⁵N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways. Moreover, their longT₁allows hyperpolarized states to be retained for up to tens of minutes. Signal amplification by reversible exchange (SABRE) is a low‐cost and ultrafast hyperpolarization technique that has been shown to be versatile for the hyperpolarization of¹⁵N nuclei. Although large sensitivity gains are enabled by hyperpolarization,¹⁵N natural abundance is only ∼0.4 %, so isotopic labeling of the molecules to be hyperpolarized is required in order to take full advantage of the hyperpolarized state. Herein, we describe selected advances in the preparation of¹⁵N‐labeled compounds with the primary emphasis on using these compounds for SABRE polarization in microtesla magnetic fields through spontaneous polarization transfer from parahydrogen. Also, these principles can certainly be applied for hyperpolarization of these emerging contrast agents using dynamic nuclear polarization and other techniques.

 

Many MRI contrast agents formed with the parahydrogen‐induced polarization (PHIP) technique exhibit biocompatible profiles. In the context of respiratory imaging with inhalable molecular contrast agents, the development of nonflammable contrast agents would nonetheless be highly beneficial for the biomedical translation of this sensitive, high‐throughput and affordable hyperpolarization technique. To this end, we assess the hydrogenation kinetics, the polarization levels and the lifetimes of PHIP hyperpolarized products (acids, ethers and esters) at various degrees of fluorine substitution. The results highlight important trends as a function of molecular structure that are instrumental for the design of new, safe contrast agents for in vivo imaging applications of the PHIP technique, with an emphasis on the highly volatile group of ethers used as inhalable anesthetics.

 

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 three¹⁵N sites of [¹⁵N₃]nimorazole with T₁of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000‐fold at 1.4 T (corresponding toP_15Nof 3.2 %) by¹⁵N−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.