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.

19F Magic Angle Spinning Dynamic Nuclear Polarization Enhanced NMR Spectroscopy

“…Here,w ei ntroduce ap rotocol for efficient hyperpolarization of 19 Fn uclei in MAS DNP enhanced NMR spectroscopy. Here,w ei ntroduce ap rotocol for efficient hyperpolarization of 19 Fn uclei in MAS DNP enhanced NMR spectroscopy.…”

“…[2e] APIs are typically organic molecules containing heteronuclei such as C, N, O, P, S, and halogens.Carbon-13 is agood NMR probe for organic materials,b ut resolution can be limited by signal overlap in complex mixtures.Asmany APIs are hydrochloride salts in their dosage form, 35/37 Cl DNP protocols have been developed for acquiring full powder pattern spectra of microcrystalline solids with high sensitivity. However,n or obust protocol has been reported thus far for 19 FD NP enhanced solid-state NMR spectroscopy.In2010 about 20 %ofall APIs used contained at least one fluorine atom; [10] in recent years, this percentage has increased up to about 30 %, and continued growth is expected. However,n or obust protocol has been reported thus far for 19 FD NP enhanced solid-state NMR spectroscopy.In2010 about 20 %ofall APIs used contained at least one fluorine atom; [10] in recent years, this percentage has increased up to about 30 %, and continued growth is expected.…”

“…Cross-effect (CE) DNP is currently the most efficient electron to nuclear polarization transfer mechanism when operating at low temperature (100 K) and moderate fields (e.g., 9.4 T). [1a, 6a, 15] Nevertheless, this approach is not convenient for 1 H- 19 FC P, as it would require aDNP probe capable of simultaneously irradiating 1 H and 19 Fi no rder to achieve 1 H- 19 Fc ross-polarization, and where the 1 H- 19 FC Ps tep might be as ource of polarization loss. [8a] Finally,t his enhanced 1 Hp olarization can be transferred to heteronuclei by CP in indirect or relayed DNP.S ubstantial gains in sensitivity have been reported for nuclei such as 13 C, 15 N, 17 O, 29 Si, and 27 Al using indirect DNP.…”

“…In this case,abiradical polarizing agent, such as TOTAPOL, [12] AMUPol, [13] or TEKPol, [14] is utilized as as ource of unpaired electrons.S aturation of the EPR transition of the unpaired electrons of ab iradical leads to spontaneous polarization transfer from the electrons to the hyperfine-coupled nuclei nearby,t ypically protons.S pontaneous 1 H-1 Hs pin diffusion distributes the proton hyperpolarization over the whole nuclear bath, making it possible to enhance polarization of nuclei further from the polarizing agent (in a12mm frozen solution of AMUPol, around 60 %of the protons are hyperpolarized through spin diffusion). 19 FDNP has been previously realized in solution using the Overhauser effect (OE DNP) with nitroxide and BDPA radicals and at low magnetic field strengths (0.3-3 T), [16] in different solvents such as fluorinated benzenes, [17] and for different solutes such as small fluorinated molecules. [1a, 6a, 15] Nevertheless, this approach is not convenient for 1 H- 19 FC P, as it would require aDNP probe capable of simultaneously irradiating 1 H and 19 Fi no rder to achieve 1 H- 19 Fc ross-polarization, and where the 1 H- 19 FC Ps tep might be as ource of polarization loss.…”

“…[1a, 6a, 15] Nevertheless, this approach is not convenient for 1 H- 19 FC P, as it would require aDNP probe capable of simultaneously irradiating 1 H and 19 Fi no rder to achieve 1 H- 19 Fc ross-polarization, and where the 1 H- 19 FC Ps tep might be as ource of polarization loss. [19] Hilty and co-workers have demonstrated that 19 Fd issolution DNP improves throughput by af actor of four, and have determined the binding affinities between trypsin and the ligands benzamidine/benzylamine. [18] A 19 F hyperpolarization strategy relying on reversible exchange with parahydrogen (SABRE) has been reported for anumber of fluorinated heterocyclic compounds.…”