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Title: Synthetic routes to the tumour proliferation biomarker FLT and ProTide analogues for PET imaging
Author: Velanguparackel, Winnie
ISNI:       0000 0004 5351 6537
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2014
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Being one of the most rapidly advancing cancer imaging techniques in recent years, Positron Emission Tomography (PET) represents a standard of excellence with respect to sensitivity and resolution for the non-invasive in vivo molecular imaging of solid tumours via the detection of radiotracer molecules. Amongst these radiotracers, radiolabelled fluorinated nucleosides such as 3’-Deoxy-3’-[18F]-fluorothymidine (18F-FLT) has been widely recognized as a key, specific biomarker for tumour cellular proliferation. Current methods for the commercial production of [18F]FLT are characterized by low overall yields and time-consuming high-performance liquid chromatography (HPLC) purification. These disadvantages could be rectified by the development of a fast, efficient synthetic route to FLT that could enhance the productivity and reduce the reaction time of the fluoridation step necessary for the synthesis of short-lived radioisotope, 18F (t1/2=110 min) installed nucleoside. This project focussed mainly on the development of a new efficient chemical synthetic route to FLT. The synthesis and in vitro evaluation of a series of pro-nucleotide (ProTide) analogues of FLT as new potential therapeutic agents was also carried out. Various studies regarding FLT synthesis have been carried out on the cold (non-radioactive) 19F and radioactive 18F isomer by varying and optimizing conditions for the incorporation of different protecting groups and also different fluoridation reactions by nucleophilic displacement. Further optimization studies were made for the fluoridation step and the synthesis of [18F]FLTProTide analogues as new diagnostic PET imaging agents by variation of different chemical parameters on the phosphoramidate group was attempted. The synthesis of 19F- FLT based ProTides as new therapeutic agents were initiated by the introduction of the phosphoramidate group at the 5’-position of the furanosyl group of thymidine under basic conditions followed by fluoridation to generate the desired analogues. In addition to that, biological evaluation of the newly developed 19F-FLT ProTide analogues for anti-HIV 1 and anti-HIV 2 activities was undertaken on CEM cells. The results in those models indicated that the synthesized compounds were less potent than the parent nucleoside FLT. However in TK- (HIV-2) cells, the analogues retained biological activity in contrast to FLT. This suggested that the FLT ProTides bypassed the first phosphorylation step. However, the therapeutic in vitro evaluation for anti-tumour activity on L1210, CEM and HeLa cells showed no significant activity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry ; RM Therapeutics. Pharmacology