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- aggregation classification "D1".
- aggregation creator person.
- aggregation date "2012".
- aggregation format "application/pdf".
- aggregation hasFormat 3169207.bibtex.
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- aggregation language "eng".
- aggregation publisher "Ghent University. Faculty of Pharmaceutical Sciences".
- aggregation rights "I have transferred the copyright for this publication to the publisher".
- aggregation subject "Medicine and Health Sciences".
- aggregation title "[18F]Fluoromethylcholine and analogues: synthesis, in vitro and in vivo evaluation, and kinetic modelling".
- aggregation abstract "To date, the tracer most used for molecular imaging in oncology is [18F]FDG. Despite its clinical use for the visualisation of various types of cancers, [18F]FDG displays several shortcomings including uptake in brown fat or inflamed tissues, high urinary clearance or brain uptake, and low uptake in poorly differentiated tumours. This rationalizes the drive to develop new tracers that are based on other metabolic pathways like protein synthesis, tumour cell proliferation, or fatty acid synthesis. In this respect, [18F]FCho is a promising alternative because its uptake in tumour cell is correlated to up regulated and elevated levels of choline kinase and choline transporters. Due to the affinity for the kinase enzyme, choline is metabolically trapped in tumour cells with superior imaging properties as result. To further elaborate the potential of [18F]FCho as radiotracer, a semi-automated Scintomics synthesis module was modified for its production. However, using the prescribed synthesis procedures, we observed high levels of residual DMAE in the [18F]FCho solution thus obtained. Remarkably, few attention has been paid to this defect, especially since in previously published reports it was noted that [11C]Cho uptake was altered by the presence of residual DMAE. As a consequence, we attempted to produce [18F]FCho with higher purity (i.e., lower DMAE levels) and, in line with this, to elucidate the role of residual DMAE on [18F]FCho uptake using F98 glioma cell lines and xenograft mouse models (Chapter 3). Having a [18F]FCho preparation method available, an investigational medicinal product dossier was compiled for 2 clinical trials to be conducted using this tracer: 1) for the early detection of glioma recurrence after treatment of the primary tumour and 2) for differentiation between cirrhotic changes and malignant lesions in well-differentiated hepatocellular carcinomas (HCC). These trials required the implementation of a fully validated quality system for the production and quality control of the final [18F]FCho solution. To assure long-term stability of this procedure, a retrospective study was conducted to evaluate the quality of the produced tracer and the validated synthesis procedure. Moreover, the compliance of the synthesis procedures and quality controls with the forthcoming PIC/s regulations for hospital pharmacies was evaluated (Chapter 4). Considering the need for quantification of the radiotracer uptake to evaluate biological processes, we assumed it was appropriate to determine a proper kinetic model for [18F]FCho. The selected kinetic model was verified against the corresponding, but simplified graphical analysis to obtain a robust and reliable method that allows absolute quantification of the tracer uptake in tissues (Chapter 5). [18F]FCho is currently used for the visualisation of various tumours, but oxidative metabolisation to the corresponding betaine compromises sensitivity. The development of analogues, which are less susceptible to this oxidation, seems a feasible strategy to induce tracer uptake in the tumours with improved sensitivity. For this reason, dimethylaminoethanol (DMAE) and homocholine were labelled with [18F]fluoride and evaluated in vivo as potential biomarkers for the aberrant phospholipids metabolism. Indeed, preliminary in vitro tests indicated that [14C]- and [11C]-labelled DMAE are better tracers to visualize the tumours phospholipids metabolism, because their uptake in various tumour cells was 2 to 7-fold higher than for [14C]- and [11C]-labelled choline. Considering the better radiophysical properties of [18F]fluorinated compounds, synthesis was attempted of [18F]-labelled DMAE as a new tracer for tumour imaging (Chapter 6). On the other hand, it was published that homocholine shows reduced affinity for the choline dehydrogenase enzyme. Accordingly, evaluation of radiolabelled homocholine and its analogues as potential biomarkers for the aberrant phospholipids metabolism was aimed at (Chapter 7).".
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