Monday, November 12, 2018

NMR Spectroscopy Unchained: Attaining the Highest Signal Enhancements in Dissolution Dynamic Nuclear Polarization #DNPNMR

Niedbalski, Peter, Andhika Kiswandhi, Christopher Parish, Qing Wang, Fatemeh Khashami, and Lloyd Lumata. “NMR Spectroscopy Unchained: Attaining the Highest Signal Enhancements in Dissolution Dynamic Nuclear Polarization.” The Journal of Physical Chemistry Letters 9, no. 18 (September 20, 2018): 5481–89.

Dynamic nuclear polarization (DNP) via the dissolution method is one of the most successful methods for alleviating the inherently low Boltzmann-dictated sensitivity in nuclear magnetic resonance (NMR) spectroscopy. This emerging technology has already begun to positively impact chemical and metabolic research by providing the much-needed enhancement of the liquid-state NMR signals of insensitive nuclei such as 13C by several thousand-fold. In this Perspective, we present our viewpoints regarding the key elements needed to maximize the NMR signal enhancements in dissolution DNP, from the very core of the DNP process at cryogenic temperatures, DNP instrumental conditions, and chemical tuning in sample preparation to current developments in minimizing hyperpolarization losses during the dissolution transfer process. The optimization steps discussed herein could potentially provide important experimental and theoretical considerations in harnessing the best possible sensitivity gains in NMR spectroscopy as afforded by optimized dissolution DNP technology.

Friday, November 9, 2018

Computationally Assisted Design of Polarizing Agents for Dynamic Nuclear Polarization Enhanced NMR: The AsymPol Family #DNPNMR

Mentink-Vigier, Frédéric, Ildefonso Marin-Montesinos, Anil P. Jagtap, Thomas Halbritter, Johan van Tol, Sabine Hediger, Daniel Lee, Snorri Th. Sigurdsson, and Gaël De Paëpe. “Computationally Assisted Design of Polarizing Agents for Dynamic Nuclear Polarization Enhanced NMR: The AsymPol Family.” Journal of the American Chemical Society 140, no. 35 (September 5, 2018): 11013–19.

We introduce a new family of highly efficient polarizing agents for dynamic nuclear polarization (DNP)-enhanced nuclear magnetic resonance (NMR) applications, composed of asymmetric bis-nitroxides, in which a piperidine-based radical and a pyrrolinoxyl or a proxyl radical are linked together. The design of the AsymPol family was guided by the use of advanced simulations that allow computation of the impact of the radical structure on DNP efficiency. These simulations suggested the use of a relatively short linker with the intention to generate a sizable intramolecular electron dipolar coupling/J-exchange interaction, while avoiding parallel nitroxide orientations. The characteristics of AsymPol were further tuned, for instance with the addition of a conjugated carbon−carbon double bond in the 5-membered ring to improve the rigidity and provide a favorable relative orientation, the replacement of methyls by spirocyclohexanolyl groups to slow the electron spin relaxation, and the introduction of phosphate groups to yield highly water-soluble dopants. An in-depth experimental and theoretical study for two members of the family, AsymPol and AsymPolPOK, is presented here. We report substantial sensitivity gains at both 9.4 and 18.8 T. The robust efficiency of this new family is further demonstrated through high-resolution surface characterization of an important industrial catalyst using fast sample spinning at 18.8 T. This work highlights a new direction for polarizing agent design and the critical importance of computations in this process.

Wednesday, November 7, 2018

Photogenerated Radical in Phenylglyoxylic Acid for in Vivo Hyperpolarized 13C MR with Photosensitive Metabolic Substrates #DNPNMR

Marco-Rius, Irene, Tian Cheng, Adam P. Gaunt, Saket Patel, Felix Kreis, Andrea Capozzi, Alan J. Wright, Kevin M. Brindle, Olivier Ouari, and Arnaud Comment. “Photogenerated Radical in Phenylglyoxylic Acid for in Vivo Hyperpolarized 13 C MR with Photosensitive Metabolic Substrates.” Journal of the American Chemical Society 140, no. 43 (October 31, 2018): 14455–63.

Whether for 13C magnetic resonance studies in chemistry, biochemistry or biomedicine, hyperpolarization methods based on dynamic nuclear polarization (DNP) have become ubiquitous. DNP requires a source of unpaired electrons, which are commonly added to the sample to be hyperpolarized in the form of stable free radicals. Once polarized, the presence of these radicals is unwanted. These radicals can be replaced by nonpersistent radicals created by photo-irradiation of pyruvic acid (PA), which are annihilated upon dissolution or thermalization in the solid state. However, since PA is readily metabolized by most cells, its presence may be undesirable for some metabolic studies. In addition, some 13C substrates are photo-sensitive and, therefore, may degrade during photo-generation of PA radical, which requires ultraviolet (UV) light. We show here that photoirradiation of phenylglyoxylic acid (PhGA) using visible light produces a non-persistent radical that, in principle, can be used to hyperpolarize any molecule. We compare radical yields in samples containing PA and PhGA upon photo-irradiation with broadband and narrowband UV-visible light sources. To demonstrate the suitability of PhGA as a radical precursor for DNP, we polarized the gluconeogenic probe 13C-dihydroxyacetone, which is UV-sensitive, using a commercial 3.35 T DNP polarizer and then injected this into a mouse and followed its metabolism in vivo.

Monday, November 5, 2018

Adiabatic-NOVEL for Nano-Scale Magnetic Resonance Imaging #DNPNMR

Annabestani, Razieh, Maryam Mirkamali, and Raffi Budakian. “Adiabatic-NOVEL for Nano-Scale Magnetic Resonance Imaging.” ArXiv:1712.09128 [Quant-Ph], December 25, 2017.

We propose a highly efficient dynamic nuclear polarization technique that is robust against field in-homogeneity. This technique is designed to enhance the detection sensitivity in nano-MRI, where large Rabi field gradients are required. The proposed technique consists of an adiabatic half passage pulse followed by an adiabatic linear sweep of the electron Rabi frequency and can be considered as an adiabatic version of nuclear orientation via electron spin locking (adiabatic-NOVEL). We analyze the spin dynamics of an electron-nuclear system that is under microwave irradiation at high static magnetic field and at cryogenic temperature. The result shows that an amplitude modulation of the microwave field makes adiabatic-NOVEL highly efficient and robust against both the static and microwave field in-homogeneity.

Friday, November 2, 2018

Determination of binding affinities using hyperpolarized NMR with simultaneous 4-channel detection

Kim, Yaewon, Mengxiao Liu, and Christian Hilty. “Determination of Binding Affinities Using Hyperpolarized NMR with Simultaneous 4-Channel Detection.” Journal of Magnetic Resonance 295 (October 2018): 80–86.

Dissolution dynamic nuclear polarization (D-DNP) is a powerful technique to improve NMR sensitivity by a factor of thousands. Combining D-DNP with NMR-based screening enables to mitigate solubility or availability problems of ligands and target proteins in drug discovery as it can lower the concentration requirements into the sub-micromolar range. One of the challenges that D-DNP assisted NMR screening methods face for broad application, however, is a reduced throughput due to additional procedures and time required to create hyperpolarization. These requirements result in a delay of several tens of minutes in-between each NMR measurement. To solve this problem, we have developed a simultaneous 4-channel detection method for hyperpolarized 19F NMR, which can increase throughput four-fold utilizing a purpose-built multiplexed NMR spectrometer and probe. With this system, the concentration-dependent binding interactions were observed for benzamidine and benzylamine with the serine protease trypsin. A T2 relaxation measurement of a hyperpolarized reporter ligand (TFBC; CF3C6H4CNHNH2), which competes for the same binding site on the trypsin with the other ligands, was used. The hyperpolarized TFBC was mixed with trypsin and the ligand of interest, and injected into four flow cells inside the NMR probe. Across the set of four channels, a concentration gradient was created. From the simultaneously acquired relaxation datasets, it was possible to determine the dissociation constant (KD) of benzamidine or benzylamine without the requirement for individually optimizing experimental conditions for different affinities. A simulation showed that this 4-channel detection method applied to D-DNP NMR extends the screenable KD range to up to three orders of magnitude in a single experiment.

Wednesday, October 31, 2018

Monitoring of hydrogenation by benchtop NMR with parahydrogen-induced polarization

Jeong, Keunhong, Sein Min, Heelim Chae, and Sung Keon Namgoong. “Monitoring of Hydrogenation by Benchtop NMR with Parahydrogen-Induced Polarization.” Magnetic Resonance in Chemistry, August 29, 2018.

Reaction monitoring using nuclear magnetic resonance (NMR) spectroscopy is a powerful tool that provides detailed information on the characteristics and mechanism of the reaction. Although highfield NMR provides more accurate and abundant data, which can be explained in terms of Boltzmann factors, benchtop NMR is commonly used because of its low cost and simple maintenance. Therefore, hyperpolarization of the sample in benchtop NMR is a suitable protocol for real-time reaction monitoring. Herein, the principle-based experimental setup, integrating the reaction monitoring system in a 60-MHz benchtop NMR instrument with a parahydrogen-induced polarization (PHIP) system, is used. Enhanced signals by the ALTADENA mechanism were obtained after PHIP on styrene, and reasonable kinetic data were collected, supporting the known reactivity of Wilkinson’s catalyst. These results should provide a foundation for future applications of NMR-based reaction monitoring systems utilizing hyperpolarization.

Monday, October 29, 2018

A portable ventilator with integrated physiologic monitoring for hyperpolarized 129Xe MRI in rodents

Virgincar, Rohan S., Jerry Dahlke, Scott H. Robertson, Nathann Morand, Yi Qi, Simone Degan, Bastiaan Driehuys, and John C. Nouls. “A Portable Ventilator with Integrated Physiologic Monitoring for Hyperpolarized 129Xe MRI in Rodents.” Journal of Magnetic Resonance 295 (October 2018): 63–71.

Hyperpolarized (HP) 129Xe MRI is emerging as a powerful, non-invasive method to image lung function and is beginning to find clinical application across a range of conditions. As clinical implementation progresses, it becomes important to translate back to well-defined animal models, where novel disease signatures can be characterized longitudinally and validated against histology. To date, preclinical 129Xe MRI has been limited to only a few sites worldwide with 2D imaging that is not generally sufficient to fully capture the heterogeneity of lung disease. To address these limitations and facilitate broader dissemination, we report on a compact and portable HP gas ventilator that integrates all the gas-delivery and physiologic monitoring capabilities required for high-resolution 3D hyperpolarized 129Xe imaging. This ventilator is MR- and HP-gas compatible, driven by inexpensive microcontrollers and open source code, and allows for precise control of the tidal volume and breathing cycle in perorally intubated mice and rats. We use the system to demonstrate data acquisition over multiple breath-holds, during which lung motion is suspended to enable high-resolution 3D imaging of gas-phase and dissolved-phase 129Xe in the lungs. We demonstrate the portability and versatility of the ventilator by imaging a mouse model of lung cancer longitudinally at 2-Tesla, and a healthy rat at 7 T. We also report the detection of subtle spectroscopic fluctuations in phase with the heart rate, superimposed onto larger variations stemming from the respiratory cycle. This ventilator was developed to facilitate duplication and gain broad adoption to accelerate preclinical 129Xe MRI research.