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Abstract Imaging of gases is a major challenge for any modality including MRI. NMR and MRI signals are directly proportional to the nuclear spin density and the degree of alignment of nuclear spins with applied static magnetic field, which is called nuclear spin polarization. The level of nuclear spin polarization is typically very low, i.e., one hundred thousandth of the potential maximum at 1.5 T and a physiologically relevant temperature. As a result, MRI typically focusses on imaging highly concentrated tissue water. Hyperpolarization methods transiently increase nuclear spin polarizations up to unity, yielding corresponding gains in MRI signal level of several orders of magnitude that enable the 3D imaging of dilute biomolecules including gases. Parahydrogen‐induced polarization is a fast, highly scalable, and low‐cost hyperpolarization technique. The focus of this Minireview is to highlight selected advances in the field of parahydrogen‐induced polarization for the production of hyperpolarized compounds, which can be potentially employed as inhalable contrast agents. 

Abstract 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. 

Abstract 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. 

Abstract 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. 

Abstract The growing interest in magnetic resonance imaging (MRI) for assessing regional lung function relies on the use of nuclear spin hyperpolarized gas as a contrast agent. The long gas‐phase lifetimes of hyperpolarized¹²⁹Xe make this inhalable contrast agent acceptable for clinical research today despite limitations such as high cost, low throughput of production and challenges of¹²⁹Xe imaging on clinical MRI scanners, which are normally equipped with proton detection only. We report on low‐cost and high‐throughput preparation of proton‐hyperpolarized diethyl ether, which can be potentially employed for pulmonary imaging with a nontoxic, simple, and sensitive overall strategy using proton detection commonly available on all clinical MRI scanners. Diethyl ether is hyperpolarized by pairwise parahydrogen addition to vinyl ethyl ether and characterized by¹H NMR spectroscopy. Proton polarization levels exceeding 8 % are achieved at near complete chemical conversion within seconds, causing the activation of radio amplification by stimulated emission radiation (RASER) throughout detection. Although gas‐phaseT₁relaxation of hyperpolarized diethyl ether (at partial pressure of 0.5 bar) is very efficient, withT₁of ca. 1.2 second, we demonstrate that, at low magnetic fields, the use of long‐lived singlet states created via pairwise parahydrogen addition extends the relaxation decay by approximately threefold, paving the way to bioimaging applications and beyond.