Signal amplification by reversible exchange (SABRE) is an established route for the efficient hyperpolarisation and therefore improved signal visibility of compounds with NMR. Recent developments in the SABRE process have now extended the variety of applicable compounds and chemical motifs (including pyruvate, glucose and other important bio-molecules). In turn this has opened up exciting potential clinical applications in spectroscopic imaging of function metabolism in-vivo, the realisation of which requires immediate imaging technology development.
In general, for all imaging nuclei, current spectroscopic acquisition methods are often inadequate in several aspects. Conventional excitation and refocusing RF pulses for spatial localisation of specific compounds can suffer from chemical shift mis-registration and image artefacts result confounding the data. Furthermore, the fast nature of capturing the quickly decaying hyperpolarised signals pushes peak RF power requirements to levels exceeding hardware limits thus potentially damaging expensive equipment. The short T1 relaxation times of the hyperpolarised agents also limits detection (a few seconds) to fast analysis of kinetic flux rates. Longer term measurements through dual probe labelling with optical markers will improve method efficacy for in-vivo basic science. Specific to 1H based SABRE, imaging in-vivo also requires optimal endogenous spin (water/fat) suppression as to not mask the compounds of interest. Partial suppression of the water pool during SABRE experiments can also provide valuable phase/frequency reference points for data analysis and an assessment of experimental success in cases in which all SABRE resonances are normally undetectable.
To improve the scope of SABRE based imaging this project will:
• Develop and implement independent flip angle controlled spectral-spatial RF pulses to negate chemical shift mis-registration errors and to provide dual-band excitation with partial excitation of the water resonance and full excitation of the metabolites of interest.
• Implement strategies to lower RF power usage by at least 30% – including exploration and optimisation of phase modulation.
• Synthesise dual labelled agents with long life optical markers to allow both short term kinetic flux measurements (SABRE) and long term compound tracking (optically). This will improve the efficacy of in-vivo measurements and open opportunities for wider in-vivo basic research applications.
The SABRE process for relevant synthesised compounds (e.g. pyruvate/glucose/nicotinamide) will be optimised for both 1H and 13C based MR spectroscopic imaging. The proposed acquisition developments will be tested through the study of short/long term functional metabolic processes in brain using innovative concurrent preclinical high field 7T MRI and 2D optical imaging spectroscopy techniques. MR spectroscopic imaging using multi-band RF pulses will be tested/compared to imaging with standard narrow band RF pulses. MR and optical data will be used in mathematical models (one way and two-way exchange models) to extract kinetic parameters/rate constants.
Novelty: This multidisciplinary project will for the first time bring together innovative SABRE hyperpolarised chemistry, photochemistry based spectroscopy with advanced physical engineering of RF to deliver a pioneering research tool which can help further our mechanistic understanding of the effect if biochemical environment in brain across health and disease.
The student will initially be introduced to chemical synthesis, catalysis and hyperpolarisation of the agents for the SABRE process. They will learn about 1H and X-nuclei NMR detection of these agents before expanding detection into the imaging regime. Training for imaging on high field 7T/9.4T preclinical MRI system and visible-wavelength spectroscopic photochemistry techniques to investigate in-vivo biological metabolism will be given. Development of programming techniques in the MATLAB framework will be essential for subsequent signal processing of resulting multimodal spatial-spectra data. Formal UK Home Office training for all in-vivo work will be sought.
All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/
. This PhD project is available to study full-time or part-time (50%).
This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.