Parahydrogen-Induced Polarization of N Nuclei.

Hyperpolarization techniques provide a dramatic increase in sensitivity of nuclear magnetic resonance spectroscopy and imaging. In spite of the outstanding progress in solution-state hyperpolarization of spin-1/2 nuclei, hyperpolarization of quadrupolar nuclei remains challenging. Here, hyperpolarization of quadrupolar N nuclei with natural isotopic abundance of >99 % is demonstrated.

Antifungal Activity of N-Arylbenzoquinaldinium Derivatives against a Clinical Strain of .

Background: (Bodin, 1902) is a dermatophyte, which is widely represented in the developing and the developed world alike. Commonly transmitted from domestic animals it is particularly dangerous for immunosuppressed patients due to AIDS, cancer or transplant surgery. Search for new perspective antimycotic derivatives becomes an urgent task in the disease containment.

Hyperpolarizing DNA Nucleobases via NMR Signal Amplification by Reversible Exchange.

The present work investigates the potential for enhancing the NMR signals of DNA nucleobases by parahydrogen-based hyperpolarization. Signal amplification by reversible exchange (SABRE) and SABRE in Shield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) of selected DNA nucleobases is demonstrated with the enhancement () of H, N, and/or C spins in 3-methyladenine, cytosine, and 6-O-guanine. Solutions of the standard SABRE homogenous catalyst Ir(1,5-cyclooctadeine)(1,3-bis(2,4,6-trimethylphenyl)imidazolium)Cl ("IrIMes") and a given nucleobase in deuterated ethanol/water solutions yielded low H values (≤10), likely reflecting weak catalyst binding.

Low-Cost High-Pressure Clinical-Scale 50% Parahydrogen Generator Using Liquid Nitrogen at 77 K.

We report on a robust and low-cost parahydrogen generator design employing liquid nitrogen as a coolant. The core of the generator consists of catalyst-filled spiral copper tubing, which can be pressurized to 35 atm. Parahydrogen fraction >48% was obtained at 77 K with three nearly identical generators using paramagnetic hydrated iron oxide catalysts.

Heterogeneous H and C Parahydrogen-Induced Polarization of Acetate and Pyruvate Esters.

Magnetic resonance imaging of [1- C]hyperpolarized carboxylates (most notably, [1- C]pyruvate) allows one to visualize abnormal metabolism in tumors and other pathologies. Herein, we investigate the efficiency of H and C 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- C-enriched forms with parahydrogen over Rh/TiO catalysts in methanol-d and in D O. The maximum obtained H polarization was 0.

Synthetic Approaches for N-Labeled Hyperpolarized Heterocyclic Molecular Imaging Agents for N NMR Signal Amplification by Reversible Exchange in Microtesla Magnetic Fields.

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 imaging in vivo. Several hyperpolarization techniques exist for hyperpolarization of a large repertoire of nuclear spins, although the C and N sites of biocompatible agents are the key targets due to their widespread use in biochemical pathways.

Rational ligand choice extends the SABRE substrate scope.

Here we report on chelating ligands for Signal Amplification By Reversible Exchange (SABRE) catalysts that permit hyperpolarisation on otherwise sterically hindered substrates. We demonstrate H enhancements of ∼100-fold over 8.5 T thermal for 2-substituted pyridines, and smaller, yet significant enhancements for provitamin B and caffeine.

Effects of Deuteration of C-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-phosphoenolpyruvate and 1-C-phosphoenolpyruvate-d for application in hyperpolarized imaging technology. The 1-C-phosphoenolpyruvate-d was synthesized with 57% overall yield (over two steps), and >98% H isotopic purity, representing an improvement over the previous report. The same outcome was achieved for 1-C-phosphoenolpyruvate.

F Hyperpolarization of N-3-F-Pyridine Via Signal Amplification by Reversible Exchange.

We report synthesis of N-3-F-pyridine via Zincke salt formation with the overall 35% yield and 84% N isotopic purity. Hyperpolarization studies of Signal Amplification by Reversible Exchange (SABRE) and SABRE in SHield Enables Alignment Transfer to Heteronuclei (SABRE-SHEATH) were performed to investigate the mechanism of polarization transfer from parahydrogen-derived hydride protons to F nucleus in milli-Tesla and micro-Tesla magnetic field regimes in N-3-F-pyridine and N-3-F-pyridine. We found the mismatch between N and F magnetic field hyperpolarization profiles in the micro-Tesla regime indicating that the spontaneous hyperpolarization process likely happens directly from parahydrogen-derived hydride protons to F nucleus without spin-relaying via N site.

Parahydrogen-Induced Polarization of 1-C-Acetates and 1-C-Pyruvates Using Sidearm Hydrogenation of Vinyl, Allyl, and Propargyl Esters.

C-hyperpolarized carboxylates, such as pyruvate and acetate, are emerging molecular contrast agents for MRI visualization of various diseases, including cancer. Here we present a systematic study of H and C parahydrogen-induced polarization of acetate and pyruvate esters with ethyl, propyl and allyl alcoholic moieties. It was found that allyl pyruvate is the most efficiently hyperpolarized compound from those under study, yielding 21% and 5.

Quasi-Resonance Fluorine-19 Signal Amplification by Reversible Exchange.

We report on an extension of the quasi-resonance (QUASR) pulse sequence used for signal amplification by reversible exchange (SABRE), showing that we may target distantly -coupled F-spins. Polarization transfer from the parahydrogen-derived hydrides to the F nucleus is accomplished via weak five-bond -couplings using a shaped QUASR radio frequency pulse at a 0.05 T magnetic field.

Hyperpolarizing Concentrated Metronidazole NO Group over Six Chemical Bonds with More than 15 % Polarization and a 20 Minute Lifetime.

The NMR hyperpolarization of uniformly N-labeled [ N ]metronidazole is demonstrated by using SABRE-SHEATH. In this antibiotic, the NO group is hyperpolarized through spin relays created by N spins in [ N ]metronidazole, and the polarization is transferred from parahydrogen-derived hydrides over six chemical bonds. In less than a minute of parahydrogen bubbling at approximately 0.

Facile Removal of Homogeneous SABRE Catalysts for Purifying Hyperpolarized Metronidazole, a Potential Hypoxia Sensor.

We report a simple and effective method to remove IrIMes homogeneous polarization transfer catalysts from solutions where NMR Signal Amplification By Reversible Exchange (SABRE) has been performed, while leaving intact the substrate's hyperpolarized state. Following microTesla SABRE hyperpolarization of N spins in metronidazole, addition of SiO microparticles functionalized with 3-mercaptopropyl or 2-mercaptoethyl ethyl sulfide moieties provides removal of the catalyst from solution well within the hyperpolarization decay time at 0.3 T ( >3 mins)-and enabling transfer to 9.

A versatile synthetic route to the preparation of N heterocycles.

A robust medium-scale (approximately 3 g) synthetic method for N labeling of pyridine ( N-Py) is reported based on the Zincke reaction. N enrichment in excess of 81% was achieved with approximately 33% yield. N-Py serves as a standard substrate in a wide range of studies employing a hyperpolarization technique for efficient polarization transfer from parahydrogen to heteronuclei; this technique, called SABRE (signal amplification by reversible exchange), employs a simultaneous chemical exchange of parahydrogen and a to-be-hyperpolarized substrate (e.

Quasi-Resonance Signal Amplification by Reversible Exchange.

Here we present the feasibility of NMR signal amplification by reversible exchange (SABRE) using radio frequency irradiation at low magnetic field (0.05 T) in the regime where the chemical shifts of free and catalyst-bound species are similar. In SABRE, the N-containing substrate and parahydrogen perform simultaneous chemical exchange on an iridium hexacoordinate complex.

Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-C-Acetates and 1-C-Pyruvates via Side Arm Hydrogenation.

Hyperpolarized forms of 1-C-acetates and 1-C-pyruvates are used as diagnostic contrast agents for molecular imaging of many diseases and disorders. Here, we report the synthetic preparation of 1-C 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-C-acetates and 1-C-pyruvates via parahydrogen-induced polarization (PHIP).

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 ( > 20%) in one minute.

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.

Parahydrogen-Based Hyperpolarization for Biomedicine.

Magnetic resonance (MR) is one of the most versatile and useful physical effects used for human imaging, chemical analysis, and the elucidation of molecular structures. However, its full potential is rarely used, because only a small fraction of the nuclear spin ensemble is polarized, that is, aligned with the applied static magnetic field. Hyperpolarization methods seek other means to increase the polarization and thus the MR signal.

Aqueous, Heterogeneous Parahydrogen-Induced N Polarization.

The successful transfer of parahydrogen-induced polarization to N spins using heterogeneous catalysts in aqueous solutions was demonstrated. Hydrogenation of a synthesized unsaturated N-labeled precursor (neurine) with parahydrogen (p-H) over Rh/TiO heterogeneous catalysts yielded a hyperpolarized structural analog of choline. As a result, N polarization enhancements of over two orders of magnitude were achieved for the N-ethyl trimethyl ammonium ion product in deuterated water at elevated temperatures.

Imaging of Biomolecular NMR Signals Amplified by Reversible Exchange with Parahydrogen Inside an MRI Scanner.

The Signal Amplification by Reversible Exchange (SABRE) technique employs exchange with singlet-state parahydrogen to efficiently generate high levels of nuclear spin polarization. Spontaneous SABRE has been shown previously to be efficient in the milli-Tesla and micro-Tesla regimes. We have recently demonstrated that high-field SABRE is also possible, where proton sites of molecules that are able to reversibly coordinate to a metal center can be hyperpolarized directly within high-field magnets, potentially offering the convenience of hyperpolarization-based spectroscopy and imaging without sample shuttling.

A pulse programmable parahydrogen polarizer using a tunable electromagnet and dual channel NMR spectrometer.

Applications of parahydrogen induced polarization (PHIP) often warrant conversion of the chemically-synthesized singlet-state spin order into net heteronuclear magnetization. In order to obtain optimal yields from the overall hyperpolarization process, catalytic hydrogenation must be tightly synchronized to subsequent radiofrequency (RF) transformations of spin order. Commercial NMR consoles are designed to synchronize applied waves on multiple channels and consequently are well-suited as controllers for these types of hyperpolarization experiments that require tight coordination of RF and non-RF events.

High-resolution hyperpolarized in vivo metabolic C spectroscopy at low magnetic field (48.7mT) following murine tail-vein injection.

High-resolution C NMR spectroscopy of hyperpolarized succinate-1-C-2,3-d is reported in vitro and in vivo using a clinical-scale, biplanar (80cm-gap) 48.7mT permanent magnet with a high homogeneity magnetic field. Non-localized C NMR spectra were recorded at 0.

Long-Lived C Nuclear Spin States Hyperpolarized by Parahydrogen in Reversible Exchange at Microtesla Fields.

Parahydrogen is an inexpensive and readily available source of hyperpolarization used to enhance magnetic resonance signals by up to four orders of magnitude above thermal signals obtained at ∼10 T. A significant challenge for applications is fast signal decay after hyperpolarization. Here we use parahydrogen-based polarization transfer catalysis at microtesla fields (first introduced as SABRE-SHEATH) to hyperpolarize C spin pairs and find decay time constants of 12 s for magnetization at 0.

Toward Hyperpolarized F Molecular Imaging via Reversible Exchange with Parahydrogen.

Fluorine-19 has high NMR detection sensitivity-similar to that of protons-owing to its large gyromagnetic ratio and high natural abundance (100 %). Unlike protons, however, fluorine-19 ( F) has a negligible occurrence in biological objects, as well as a more sensitive chemical shift. As a result, in vivo F NMR spectroscopy and MR imaging offer advantages of negligible background signal and sensitive reporting of the local molecular environment.