Measurement of pH using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging

Altered metabolic phenotypes, with consequential alterations in tissue pH, are commonplace in a number of pathologies. The metabolic reprogramming common in cancer leads to acidification of the tumour microenvironment and alkalosis of the intracellular space, whereas the cessation of blood flow in ischaemic stroke results in systemic acidification of the affected tissue. Thus far, however, measurement of pH is under-utilised as a physiological parameter of interest in the clinic, despite its potential ability to measure treatment response or stratify patients to optimal therapeutic strategies. This lack of interest in pH is likely a result of a lack of non-invasive, clinically translatable measurement methods. One modality that may be able to be used for non-invasive pH measurements in vivo is Chemical Exchange Saturation Transfer (CEST) Magnetic Resonance Imaging (MRI). CEST MRI measures changes in signal from water protons owing to their association with other biomolecules and metabolites, particularly via exchange of protons in amide and amine functional groups. The rate at which chemical exchange of these protons occurs affects the measured CEST MRI signal, and is sensitive to the environmental pH. Hence, through careful calibration, CEST MRI may be used to measure pH in vivo. The development of CEST MRI to enable measurement of pH in vivo is the focus of this thesis. Firsly, novel, realistic phantom models of the in vivo intracellular environment of brain metastases and naïve mouse brain were developed to determine that the CESTR* metric with compensation for water T1 and T2 relaxation effects overcomes many challenges facing interpretation of CEST MRI data. An extension to this metric – isoCESTR* – was developed, and shown to potentially permit measurement of pH using simulated data. Subsequently, three separate animal models of human disease were used to examine the ability of isoCESTR* to measure pH. Through combination of in vivo CEST MRI data and ex vivo protein concentration measurements, tissue pHwas estimated using CEST MRI data from rats with brain metastasis and ischaemic stroke. Additionally, the pH change induced by alleviation of tumour hypoxia was measured in mice with subcutaneous tumours. Finally, a novel pulse sequence combining stimulated echo diffusion and CEST methods was developed and validated as a means of separating intra- and extracellular CEST effects. This pulse sequence was used to estimate the proportion of CEST signal originating from the intracellular space for the first time. CEST MRI is an imaging technique with great potential to permit pH measurement in vivo in clinical as well as research settings. It is hoped that the work presented here goes some way to improving the understanding of CEST effects from endogenous sources, and exploiting these effects for measurement of tissue pH.