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Periodic Reporting for period 1 - EUROPOL (EUROPOL)

Reporting period: 2015-01-01 to 2016-12-31

Nuclear Magnetic Resonance spectroscopy (NMR) and Magnetic Resonance Imaging (MRI) play unique roles in contemporary Science, from Physics, Chemistry and Biology, to clinical research and diagnosis. Further progress in NMR and MRI is hampered by sensitivities that are much lower than those of alternatives, such as mass-spectrometry and PET. The prospects of solving this problem by building “bigger machines” (e.g. relying on stronger magnets) are uncertain and may offer only a poor return, given the high level of maturity already achieved by NMR/MRI. EUROPOL challenges this status quo by combining NMR/MRI with Nuclear Hyperpolarization, which can increase signal intensities by up to x50,000. Two approaches are pursued, dynamic nuclear polarization (DNP) and para-hydrogen-driven polarization (PHIP), which have shown the greatest potential for biophysical, metabolomic, pre-clinical and clinical research. EUROPOL has assembled leading experts in the physics and engineering of magnetic resonance, in the synthetic chemistry essential for the success of these methods, and focuses on applications of hyperpolarized NMR in structural and cell biology, and in preclinical and clinical MRI applications.

Why is it important for society?
The most important aspect for society is possibility to image metabolites in an MRI setting. This has now been demonstrated in patients using hyperpolarised pyruvate. Possible applications are in cancer where a metabolic change is observed as consequence of treatment. Partners of EUROPOL are developing this application as a new potential diagnostic.

Furthermore, EUROPOL delivers a range of compounds and methods may have a wider range of applications in NMR/MRI. This may enable unprecedented analytical applications in chemistry, biochemistry, protein biochemistry and cell biology.

Overall objectives
The research objectives of the EUROPOL project are:
RO1: Methodological development of a broad-based portfolio of hyperpolarisation platforms and customised acquisition methods.
RO2: Develop the enabling chemistry required to drive biological applications of hyperpolarised MR.
RO3: High impact biomolecular studies, biological discoveries and biomedical applications, based on hyperpolarised NMR and MRI.
The work performed in the EUROPOL project in the first 2 years includes:

• Baseline metabolic profiles of 18 haemotological cancer cell lines were recorded by 1D NMR in order to perform flux analyses with a range of labelled precursors (UoB–ESR1).
• 13C to 1H polarization transfer methods have been developed and their efficiencies demonstrated both theoretically and experimentally. Novel DNP-MRI pulse sequences were used successfully used to image hyperpolarized [1-13C]lactate formation in mouse tumours in vivo via its methyl proton resonance (UCam–ESR3).
• DNP parameters have been optimised in a stand-alone polariser at low temperature. Since this project involves the use of a dual centre magnet to perform dissolution DNP, time has been invested on the understanding of hardware and software related to it, and preliminary dissolution experiments have been performed (UNott–ESR3).
• Development and application of a dual-center magnet for performing DNP-enhanced solid-state and solution-state NMR spectroscopy. DNP-enhanced solid-state NMR experiments are currently being conducted for the purposes of collecting high-quality ultra wideline NMR spectra of unreceptive nuclei. (Jaroszewicz, Frydman, & Schurko, J Phys Chem A 2017, 1, 51-65: Weizmann–ESR5).
• A series of 6 new keto acids has been designed and synthesized as candidates for non-persistent free radical polarizing agents. Their performances in generating free radical by UV-irradiation at different wavelengths and their EPR features at 9 and 35 GHz have been performed. (AMU-ESR6).
• A double tuned NMR circuit has been developed for cross-polarization as well as waveguides with lower attenuation by plating of stainless steel with lower resistance metals (DTU–ESR7).
• Analysis of the metabolic profiles of hepatocyte cell lines and metabolic flux analysis with labeled precursors (UoB–ESR9).
• In-vivo HP animal MRI experiments were conducted in which MR sequences for metabolite mapping on human scanners are being developed, with highly promising temporal and spatial resolution obtained (UKLFR–ESR10).
• The selHSQC-TOCSY method is being implemented for measurement of the magnitude and sign of J-coupling constants in molecules of interest. Moreover, HP of 15N-pyridine using SABRE and a custom made apparatus was achieved, to a level of 2 % (UKLFR–ESR11).
• Synthesis of 3 substrate ligands for hyperpolarisation experiments and have preliminary results for their long lives states and enhancements. Initial work on optimising the enhancement of pyridine for SABRE experiments (UoY–ESR12&16).
• Development of a heteronuclear CEST-based method for application in DNP hyperpolarized water experiments. A Frequency labeled exchange labeled (FLEX)-based sequence was developed (HetFLEX) to impart the heteronuclear modulation onto water and to achieve 1D 15N and 2D 15N,1H heteronuclear correlation with sensitivity enhancements (Martinho, Novakovic, Olsen, & Frydman, Angew Chem in press, 2017: Weizmann–ESR4&13).
• Preparation of isotopically labelled compounds for DNP and PHIP to be used by other partners (GUF–ESR8&14)
• An industrial applicable method for the regio and stereospecific deuterium labeling of amino acids has been developed as well as a method for regio-specific deuteration of glucopyranose (CortecNet–ESR15).
The EUROPOL project covers various developmental aspects and applications of hyperpolarisation technologies for NMR and MRI. For this EUROPOL Partners have developed new methods and improved enabling technologies.

Detection of hyperpolarized 13C-labelled substrates via their spin-coupled protons is expected to lead to a further improvement in the sensitivity of MRI of these substrates, and it is anticipated will lead eventually to translation to a clinical setting (UCam).

The identification of mechanisms in different cancer and liver cells have been explored for their metabolic turn-over and whether they are potentially amenable to DNP-enhanced metabolic imaging (UoB).

Developments in the use for solid state 19F DNP-NMR is envisioned that will lead to novel in vitro spectroscopy applications that will enable the study of rapid molecular dynamics in biomolecular systems of medical relevance (UNott).

Development of MRI methods to be used e.g. with 3T human PET-MRI systems to produce dynamic or 3D imaging data, showed a superior detection efficiency compared to standard pulse sequences used in clinical imaging systems. Progress in the field of PHIP and SABRE may dramatically lower the costs for the production of hyperpolarized contrast agents (UKLFR).