Alexandra M. Olaru

Toward Biocompatible Nuclear Hyperpolarization Using Signal Amplification by Reversible Exchange: Quantitative in Situ Spectroscopy and High-Field Imaging

Signal amplification by reversible exchange (SABRE) of a substrate and parahydrogen at a catalytic center promises to overcome the inherent insensitivity of magnetic resonance. In order to apply the new approach to biomedical applications, there is a need to develop experimental equipment, in situ quantification methods, and a biocompatible solvent. We present results detailing a low-field SABRE polarizer which provides well-controlled experimental conditions, defined spins manipulations, and which allows in situ detection of thermally polarized and hyperpolarized samples. We introduce a method for absolute quantification of hyperpolarization yield in situ by means of a thermally polarized reference. A maximum signal-to-noise ratio of ∼103 for 148 μmol of substance, a signal enhancement of 106 with respect to polarization transfer field of SABRE, or an absolute 1H-polarization level of ≈10–2 is achieved. In an important step toward biomedical application, we demonstrate 1H in situ NMR as well as 1H and 13C high-field MRI using hyperpolarized pyridine (d3) and 13C nicotinamide in pure and 11% ethanol in aqueous solution. Further increase of hyperpolarization yield, implications of in situ detection, and in vivo application are discussed.

Delivering strong 1H nuclear hyperpolarization levels and long magnetic lifetimes through signal amplification by reversible exchange

Significance The study of molecules and materials is of great significance to both science and human welfare. The noninvasive techniques of NMR and MRI reflect two of the most important methods to study them. However, both of these approaches are insensitive, and hyperpolarization methods to improve sensitivity are needed to access new applications. The hyperpolarization approach signal amplification by reversible exchange is used to produce a signal that is 100,000 times larger than that which would be seen on a routine clinical MRI scanner under Boltzmann equilibrium conditions. By revealing the broad scope of this approach we demonstrate its potential for the future diagnostic detection of metabolites, drugs, and many other small molecules. Hyperpolarization turns typically weak NMR and MRI responses into strong signals so that ordinarily impractical measurements become possible. The potential to revolutionize analytical NMR and clinical diagnosis through this approach reflect this areas most compelling outcomes. Methods to optimize the low-cost parahydrogen-based approach signal amplification by reversible exchange with studies on a series of biologically relevant nicotinamides and methyl nicotinates are detailed. These procedures involve specific 2H labeling in both the agent and catalyst and achieve polarization lifetimes of ca. 2 min with 50% polarization in the case of methyl-4,6-d2-nicotinate. Because a 1.5-T hospital scanner has an effective 1H polarization level of just 0.0005% this strategy should result in compressed detection times for chemically discerning measurements that probe disease. To demonstrate this technique’s generality, we exemplify further studies on a range of pyridazine, pyrimidine, pyrazine, and isonicotinamide analogs that feature as building blocks in biochemistry and many disease-treating drugs.

Small-scale instrumentation for nuclear magnetic resonance of porous media

The investigation of fluids confined to porous media is the oldest topic of investigation with small-scale nuclear magnetic resonance (NMR) instruments, as such instruments are mobile and can be moved to the site of the object, such as the borehole of an oil well. While the analysis was originally restricted by the inferior homogeneity of the employed magnets to relaxation measurements, today, portable magnets are available for all types of NMR measurements concerning relaxometry, imaging and spectroscopy in two types of geometries. These geometries refer to closed magnets that surround the sample and open magnets, which are brought close to the object for measurement. The current state of the art of portable, small-scale NMR instruments is reviewed and recent applications of such instruments are featured. These include the porosity analysis and description of diesel particulate filters, the determination of the moisture content in walls from gray concrete, new approaches to analyze the pore space and moisture migration in soil, and the constitutional analysis of the mortar base of ancient wall paintings.

Achieving High Levels of NMR-Hyperpolarization in Aqueous Media With Minimal Catalyst Contamination via SABRE

Abstract Signal amplification by reversible exchange (SABRE) is shown to allow access to strongly enhanced 1Hu2005NMR signals in a range of substrates in aqueous media. To achieve this outcome, phase‐transfer catalysis is exploited, which leads to less than 1.5×10−6u2005mol dm−3 of the iridium catalyst in the aqueous phase. These observations reflect a compelling route to produce a saline‐based hyperpolarized bolus in just a few seconds for subsequent in vivo MRI monitoring. The new process has been called catalyst separated hyperpolarization through signal amplification by reversible exchange or CASH‐SABRE. We illustrate this method for the substrates pyrazine, 5‐methylpyrimidine, 4,6‐d 2‐methyl nicotinate, 4,6‐d 2‐nicotinamide and pyridazine achieving 1H signal gains of approximately 790‐, 340‐, 3000‐, 260‐ and 380‐fold per proton at 9.4u2005T at the time point at which phase separation is complete.

Exchange relaxometry of flow at small Péclet numbers in a glass bead pack.

In this paper we consider low Péclet number flow in bead packs. A series of relaxation exchange experiments has been conducted and evaluated by ILT analysis. In the resulting correlation maps, we observed a collapse of the signal and a translation towards smaller relaxation times with increasing flow rates, as well as a signal tilt with respect to the diagonal. In the discussion of the phenomena we present a mathematical theory for relaxation exchange experiments that considers both diffusive and advective transport. We perform simulations based on this theory and discuss them with respect to the conducted experiments.

Extending the Scope of 19F Hyperpolarization through Signal Amplification by Reversible Exchange in MRI and NMR Spectroscopy

Abstract Fluorinated ligands have a variety of uses in chemistry and industry, but it is their medical applications as 18F‐labelled positron emission tomography (PET) tracers where they are most visible. In this work, we illustrate the potential of using 19F‐containing ligands as future magnetic resonance imaging (MRI) contrast agents and as probes in magnetic resonance spectroscopy studies by significantly increasing their magnetic resonance detectability through the signal amplification by reversible exchange (SABRE) hyperpolarization method. We achieve 19F SABRE polarization in a wide range of molecules, including those essential to medication, and analyze how their steric bulk, the substrate loading, polarization transfer field, pH, and rate of ligand exchange impact the efficiency of SABRE. We conclude by presenting 19F MRI results in phantoms, which demonstrate that many of these agents show great promise as future 19F MRI contrast agents for diagnostic investigations.

Microstructural Analysis during the Hydration of Cement-in-Polymer Coatings

Cement-in-polymer (c/p) dispersions allow the full utilisation of the reinforcing abilities of multifilament rovings in concrete. In this work the role of the polymer properties on the performance of the c/p dispersions is investigated and discussed. Two model polymers are chosen and c/p dispersions made with these are investigated regarding the water ingress velocity (NMR), the phase development during cement hydration (XRD), and the microstructure after cement hydration (SEM). Best mechanical performance is achieved with the hydrophobic poly(vinyl acetate) which regulates the water ingress and causes a slow hydration of the cement.