Density Functional Theory Study of Reaction Equilibria in Signal Amplification by Reversible Exchange

Abstract

An in-depth theoretical analysis of key chemical equilibria in Signal Amplification by Reversible Exchange (SABRE) is provided, employing density functional theory calculations to characterize the likely reaction network. For all reactions in the network, the potential energy surface is probed to identify minimum energy pathways. Energy barriers and transition states are calculated, and harmonic transition state theory is applied to calculate exchange rates that approximate experimental values. The reaction network energy surface can be modulated by chemical potentials that account for the depend-ence on concentration, temperature, and partial pressure of molecular constituents (hydrogen, methanol, pyridine) supplied to the experiment under equilibrium conditions. We show that, under typical experimental conditions, the Gibbs free energies of the two key states involved in pyridine-hydrogen exchange at the common Ir-IMes catalyst system in methanol are essentially the same, i. e., nearly optimal for SABRE. We also show that a methanol-containing intermediate is plausible as a transient species in the process.

Catalyst-Free Aqueous Hyperpolarized [1-13C]Pyruvate Obtained by Re-Dissolution Signal Amplification by Reversible Exchange

“…Although previous studies have demonstrated the direct SABRE polarization in biocompatible solvents such as aqueous media, the resulting polarization is markedly (by an order of magnitude or more) reduced compared to that in methanol, presumably due to lower hydrogen solubility and other compounding factors. − As a result, we continued with methanol as solvent for SABRE-SHEATH, and investigated the idea of performing precipitation and purification of the HP biomolecule, inspired by Eills, Knecht, and co-workers who used a related approach for fumarate. , In those studies the precipitation was achieved by adding an acid to the 13 C-hyperpolarized solutions, whereas here precipitation of pyruvate is achieved by addition of a nonpolar solvent. The present strategy may be advantageous for future clinical applications, because it avoids the use of strong acids and bases immediately before in vivo administration, which leads to additional purification and quality-assurance steps, posing translational challenges.…”

Parahydrogen in Reversible Exchange Induces Long-Lived 15N Hyperpolarization of Anticancer Drugs Anastrozole and Letrozole

“…Therefore, the faster exchanging substrate, anastrozole, will be expected to reach maximum hyperpolarization at lower temperatures relative to the faster exchanging substrate, letrozole. We note that the substrate exchange rate also controls the hydride exchange rate, as we have shown with ab initio calculations because hydride exchange does require substrate exchange events for monodentate ligands. These findings not only support that temperature modulation represents a key hyperpolarization parameter but also additionally suggest that relative exchange rates can be unveiled through HP temperature studies.…”

LIGHT-SABRE Hyperpolarizes 1-13C-Pyruvate Continuously without Magnetic Field Cycling

“…Considering that all evidence points to the need for substrate dissociation before hydrogen exchange, , we needed to introduce alternative possibilities for this process: partial pyruvate dissociation (Figure b) and co-ligand elimination (Figure c). To deduce which method is more probable, DFT simulations similar to the ones made for the prototypical Ir-complex with pyridine or more detailed exchange measurements are needed. The critical conclusion from this discussion for the present work is that the observed signals predominantly stem from catalyst-bound pyruvate.…”

“…Figure 1 b,c illustrates possible exchange mechanisms that allow for hydrogen exchange without pyruvate exchange under the assumption that hydrogen exchange is an associative mechanism, as supported by previous work. 36 , 37 We hypothesize that the pyruvate-SABRE system enables efficient hydrogen exchange because the pyruvate binds in a bidentate fashion, which allows for hydrogen exchange via partial dissociation of pyruvate ( Figure 1 b), opening a binding site for parahydrogen without pyruvate exchange all the way into its free form. A less likely alternative is depicted in Figure 1 c, where DMSO dissociation allows for H 2 association and exchange.…”