Chemical exchange saturation transfer (CEST) MRI has the ability to noninvasively measure endogenous biomarkers and exogenous agents relevant to various diseases and medical conditions. My work has focused on the development of MRI pulse sequences and data analysis methods to more accurately estimate endogenous and exogenous CEST contrast measurements at 7 T and 3 T magnetic field strengths. Chapter 1 discusses the various sources of signal that have been measured with CEST MRI in the clinic, the acquisition methods used to acquire these signals, and the data analysis methods used to quantify the CEST effects from these signals. Appendix A describes the development of a respiration gated CEST pulse sequence that was ultimately used with a lung fibrosis mouse model to measure extracellular pH (pHe) of the fibrotic lesions. Appendix B describes the development of a data processing algorithm that used the Bloch equations modified for chemical exchange to generate more accurate and precise pHe estimates both at 7 T and 3 T magnetic field strengths relative to a previous data processing algorithm. Appendix C describes the development of a retrospective gating technique for the lung that generates more accurate and precise endogenous CEST contrast measurements.

Final publication is available at http://link.springer.com/article/10.1007/s11060-014-1715-8 / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19605号 / 医博第4112号 / 新制||医||1014(附属図書館) / 32641 / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 平岡 眞寛, 教授 山田 泰広 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Stroke is one of the leading causes of death and adult disability worldwide. The major therapeutic intervention for acute ischemic stroke is the administration of recombinant tissue plasminogen activator (rtPA) to help to restore blood flow to the brain. This has been shown to increase the survival rate and to reduce the disability of ischemic stroke patients. However, rtPA is associated with intracranial haemorrhage and thus its administration is currently limited to only about 5% of ischemic stroke patients. More advanced imaging techniques can be used to better stratify patients for rtPA treatment. One new imaging technique, chemical exchange saturation transfer (CEST) magnetic resonance imaging, can potentially image intracellular pH and since tissue acidification happens prior to cerebral infarction, CEST has the potential to predict ischemic injury and hence to improve patient selection. Despite this potential, most studies have generated pH-weighted rather than quantitative pH maps; the most widely used metric to quantify the CEST effect is only able to generate qualitative contrast measurements and suffers from many confounds. The greatest clinical benefit of CEST imaging lies in its ability to non-invasively measure quantitative pH values which may be useful to identify salvageable tissue. The quantitative techniques and work presented in this thesis thus provide the necessary analysis to determine whether a threshold for the quantified CEST effect or for pH exists to help to define tissue outcome following stroke; to investigate the potential of CEST for clinical stroke imaging; and subsequently to facilitate clinical translation of CEST for acute stroke management.

Magnetic Resonance Imaging (MRI) is one of noninvasive imaging and diagnostic methods in today's medicine. The most commonly measured nucleus is H1 of the water molecules present in the human body. There are also methods that use signal saturation transfer between the contrast agent and water molecules via exchangeable H1 nuclei, or use a different nucleus like F19 . Compounds that show a high potential in this area are complexes of paramagnetic ions such as Gd3+ , Eu3+ , Co2+ , Cu2+ and Ni2+ , which can affect relaxation times and chemical shifts of other atoms due to their magnetic properties. This Master's thesis focuses on ligands L1 and L2 which were prepared in the Bachelor thesis. The main focus is on preparation of complexes with selected paramagnetic ions and subsequent study of their properties relevant for a potential use as contrast agents for F19 -MRI and CEST methods. Keywords: F19 -MRI, CEST, macrocyclic ligands, coordination chemistry

ABSTRACT This work is focused on the synthesis of a family of new macrocyclic ligands with exchangeable protons on coordinating groups that could potentially serve (after complexation with suitable paramagnetic lanthanide(III) ions) as responsive contrast agents (CAs) for magnetic resonance imaging (MRI). It is expected that measurement of extracellular pH should bring information for tumorous disease diagnoses and/or for suggesting the most efficient treatment. Therefore, our attention was focused on pH-dependent CAs based on a PARAmagnetic Chemical Exchange Saturation Transfer (PARACEST) mechanism capable of reporting pH changes in tissue. The PARACEST-related properties of a series of Ln(III) complexes with the CEST effect caused by amino groups coordinated to the central Ln(III) metal ions were investigated. Such a kind of PARACEST CA is new and has had no precedent in the literature. It was shown that these Ln(III) complexes produce a pH-sensitive PARACEST effect in the pH region relevant for living systems. The study brings proof-of-principle for utilization of complexes with a linear diamine pendant arm, i.e. complexes with two exchanging proton pools, for ratiometric pH determination by MRI independently on the probe concentration. In addition, to ensure a higher kinetic inertness of the...

In ischaemic stroke a disruption of cerebral blood flow leads to impaired metabolism and the formation of an ischaemic penumbra in which tissue at risk of infarction is sought for clinical intervention. In stroke trials, therapeutic intervention has largely been based on perfusion-weighted measures, but these have not been shown to be good predictors of tissue outcome. The aim of this thesis was to develop analysis techniques for magnetic resonance imaging (MRI) of chemical exchange saturation transfer (CEST) in order to quantify metabolic signals associated with tissue fate in patients with acute ischaemic stroke. This included addressing robustness for clinical application, and developing quantitative tools that allow exploration of the in-vivo complexity. Tissue-level analyses were performed on a dataset of 12 patients who had been admitted to the John Radcliffe Hospital in Oxford with acute ischaemic stroke and recruited into a clinical imaging study. Further characterisation of signals was performed on stroke models and tissue phantoms. A comparative study of CEST analysis techniques established a model-based approach, Bloch-McConnell model analysis, as the most robust for measuring pH-weighted signals in a clinical setting. Repeatability was improved by isolating non-CEST effects which attenuate signals of interest. The Bloch-McConnell model was developed further to explore whether more biologically-precise quantification of CEST effects was both possible and necessary. The additional model complexity, whilst more reflective of tissue biology, diminished contrast that distinguishes tissue fate, implying the biology is more complex than pH alone. The same model complexity could be used reveal signal patterns associated with tissue outcome that were otherwise obscured by competing CEST processes when observed through simpler models. Improved quantification techniques were demonstrated which were sufficiently robust to be used on clinical data, but also provided insight into the different biological processes at work in ischaemic tissue in the early stages of the disease. The complex array of competing processes in pathological tissue has underscored a need for analysis tools adequate for investigating these effects in the context of human imaging. The trends herein identified at the tissue level support the use of quantitative CEST MRI analysis as a clinical metabolic imaging tool in the investigation of ischaemic stroke.