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

Irene Marco-Rius,Arnaud Comment,Tian Cheng,Adam P Gaunt,Kevin M Brindle,Saket Patel,Andrea Capozzi,Felix Kreis,Alan J Wright,Olivier Ouari

doi:10.1021/jacs.8b09326

Abstract

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 the photoirradiation 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 photosensitive and therefore may degrade during the photogeneration of a PA radical, which requires ultraviolet (UV) light. We show here that the photoirradiation of phenylglyoxylic acid (PhGA) using visible light produces a nonpersistent radical that, in principle, can be used to hyperpolarize any molecule. We compare radical yields in samples containing PA and PhGA upon photoirradiation 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.

Highlights

Hyperpolarization by dissolution dynamic nuclear polarization (DNP) can enhance the magnetic resonance (MR) signals of molecules in solution by up to 5 orders of magnitude.[1]
The spectral region around 72.3 ppm was sampled 360 times, and the region around 214 ppm was sampled 40 times. This high temporal resolution acquisition strategy was chosen to maximize the signal-to-noise ratio of the summed spectra assuming an in vivo T1 of 10 s for the metabolites. (See the analysis presented in ref 21.) A similar scheme has previously been used for the detection of glucose metabolism in vivo.[22,23]
On the basis of the multiplied spectra calculated from the UV− vis absorption of pyruvic acid (PA) and phenylglyoxylic acid (PhGA) and the wavelength-dependent power distribution of each light source, the BlueWave 75 light source was expected to be more effective for radical generation in PA while the VisiCure 405 source should be better suited for radical generation in PhGA since the ratio areabroadband/ area[405] nm is much larger for PA than for PhGA (15 vs 2.8)

Summary

Introduction

Hyperpolarization by dissolution dynamic nuclear polarization (DNP) can enhance the magnetic resonance (MR) signals of molecules in solution by up to 5 orders of magnitude.[1] As the list of molecules that have been hyperpolarized increases every year, so do applications across organic and polymer chemistry[2] as well as biomedicine.[3] DNP is based on the transfer of spin polarization from unpaired electrons of stable free radicals to nuclei at cryogenic temperatures. Medical regulatory bodies currently demand that radicals are filtered out prior to injection into a human subject,[8,9] which adds to the complexity of the process and becomes a potential failure point before the release of the solution for injection

Objectives

Results

Discussion

Conclusion