Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution

Abstract

Significance Magnetic resonance imaging is hindered by inherently low sensitivity, which limits the method for the most part to observing water molecules in the body. Hyperpolarized molecules exhibit strongly enhanced MRI signals which opens the door for imaging low-concentration species in vivo. Biomolecules can be hyperpolarized and injected into a patient allowing for metabolism to be tracked in real time, greatly expanding the information available to the radiologist. Parahydrogen-induced polarization (PHIP) is a hyperpolarization method renowned for its low cost and accessibility, but is generally limited by low polarization levels, modest molecular concentrations, and contamination by polarization reagents. In this work we overcome these drawbacks in the production of PHIP-polarized [1- 13 C]fumarate, a biomarker of cell necrosis in metabolic 13 C MRI.

Autoren

Stephan Knecht
John W Blanchard
Danila Barskiy
Eleonora Cavallari
Laurynas Dagys
Erik Van Dyke
Maksim Tsukanov
Bea Bliemel
Kerstin Münnemann
Silvio Aime
Francesca Reineri
Malcolm H Levitt
Gerd Buntkowsky
Alexander Pines
Peter Blümler
Dmitry Budker
James Eills

DOI

10.1073/pnas.2025383118

eISSN

1091-6490

ISSN

0027-8424

Ausgabe der Veröffentlichung

13

Zeitschrift

Proceedings of the National Academy of Sciences

Sprache

en

Online publication date

2021

Datum der Veröffentlichung

2021

Status

Published

Herausgeber

Proceedings of the National Academy of Sciences

Herausgeber URL

http://dx.doi.org/10.1073/pnas.2025383118

Datum der Datenerfassung

2022

Titel

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution

Ausgabe der Zeitschrift

118

Datenquelle: Crossref

Abstract

Hyperpolarized fumarate is a promising biosensor for carbon-13 magnetic resonance metabolic imaging. Such molecular imaging applications require nuclear hyperpolarization to attain sufficient signal strength. Dissolution dynamic nuclear polarization is the current state-of-the-art methodology for hyperpolarizing fumarate, but this is expensive and relatively slow. Alternatively, this important biomolecule can be hyperpolarized in a cheap and convenient manner using parahydrogen-induced polarization. However, this process requires a chemical reaction, and the resulting solutions are contaminated with the catalyst, unreacted reagents, and reaction side-product molecules, and are hence unsuitable for use in vivo. In this work we show that the hyperpolarized fumarate can be purified from these contaminants by acid precipitation as a pure solid, and later redissolved to a desired concentration in a clean aqueous solvent. Significant advances in the reaction conditions and reactor equipment allow for formation of hyperpolarized fumarate at <sup>13</sup>C polarization levels of 30-45%.

Addresses

Eduard-Zintl-Institute for Inorganic Chemistry and Physical Chemistry, Technical University Darmstadt, 64287 Darmstadt, Germany.

Autoren

Stephan Knecht
John W Blanchard
Danila Barskiy
Eleonora Cavallari
Laurynas Dagys
Erik Van Dyke
Maksim Tsukanov
Bea Bliemel
Kerstin Münnemann
Silvio Aime
Francesca Reineri
Malcolm H Levitt
Gerd Buntkowsky
Alexander Pines
Peter Blümler
Dmitry Budker
James Eills

DOI

10.1073/pnas.2025383118

eISSN

1091-6490

Externe Identifier

PubMed Identifier: 33753510
PubMed Central ID: PMC8020773

Funding acknowledgements

Engineering and Physical Sciences Research Council: EP/P030491/1
Engineering and Physical Sciences Research Council: EP/V055593/1
European Research Council: 786707
European Research Council: 858149
Engineering and Physical Sciences Research Council: EP/P009980/1
Engineering and Physical Sciences Research Council: EP/K00509X/1

Open access

true

ISSN

0027-8424

Ausgabe der Veröffentlichung

13

Zeitschrift

Proceedings of the National Academy of Sciences of the United States of America

Schlüsselwörter

Water
Fumarates
Solutions
Biosensing Techniques
Molecular Imaging
Carbon-13 Magnetic Resonance Spectroscopy

Sprache

eng

Medium

Print

Open access status

Open Access

Paginierung

e2025383118

Datum der Veröffentlichung

2021

Status

Published

Publisher licence

CC BY

Datum der Datenerfassung

2021

Titel

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution.

Sub types

Research Support, Non-U.S. Gov't
research-article
Research Support, U.S. Gov't, Non-P.H.S.
Journal Article

Ausgabe der Zeitschrift

118

Files

https://europepmc.org/articles/PMC8020773?pdf=render

Datenquelle: Europe PubMed Central

Abstract

Hyperpolarized fumarate is a promising biosensor for carbon-13 magnetic resonance metabolic imaging. Such molecular imaging applications require nuclear hyperpolarization to attain sufficient signal strength. Dissolution dynamic nuclear polarization is the current state-of-the-art methodology for hyperpolarizing fumarate, but this is expensive and relatively slow. Alternatively, this important biomolecule can be hyperpolarized in a cheap and convenient manner using parahydrogen-induced polarization. However, this process requires a chemical reaction, and the resulting solutions are contaminated with the catalyst, unreacted reagents, and reaction side-product molecules, and are hence unsuitable for use in vivo. In this work we show that the hyperpolarized fumarate can be purified from these contaminants by acid precipitation as a pure solid, and later redissolved to a desired concentration in a clean aqueous solvent. Significant advances in the reaction conditions and reactor equipment allow for formation of hyperpolarized fumarate at 13C polarization levels of 30-45%.

Autoren

Stephan Knecht
John W Blanchard
Danila Barskiy
Eleonora Cavallari
Laurynas Dagys
Erik Van Dyke
Maksim Tsukanov
Bea Bliemel
Kerstin Münnemann
Silvio Aime
Francesca Reineri
Malcolm H Levitt
Gerd Buntkowsky
Alexander Pines
Peter Blümler
Dmitry Budker
James Eills

Autoren-URL

https://www.ncbi.nlm.nih.gov/pubmed/33753510

DOI

10.1073/pnas.2025383118

eISSN

1091-6490

Externe Identifier

PubMed Central ID: PMC8020773

Ausgabe der Veröffentlichung

13

Zeitschrift

Proc Natl Acad Sci U S A

Schlüsselwörter

MRI
biomarker
hyperpolarization
metabolism
parahydrogen
Biosensing Techniques
Carbon-13 Magnetic Resonance Spectroscopy
Fumarates
Molecular Imaging
Solutions
Water

Sprache

eng

Country

United States

PII

2025383118

Datum der Veröffentlichung

2021

Status

Published

Datum, an dem der Datensatz öffentlich gemacht wurde

2021

Titel

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution.

Sub types

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Ausgabe der Zeitschrift

118

Datenquelle: PubMed

Rapid hyperpolarization and purification of the metabolite fumarate in aqueous solution

Files

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