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Radiochemical synthesis of 18F-radiolabelled ProTides for Positron Emission Tomography

Cavaliere, Alessandra 2018. Radiochemical synthesis of 18F-radiolabelled ProTides for Positron Emission Tomography. PhD Thesis, Cardiff University.
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Abstract

Positron Emission Tomography (PET) is a highly sensitive imaging technique used in cancer diagnosis, treatment planning and monitoring of therapy response. [18F] is an optimal PET label considering its half-life (110 min) and imaging resolution. One of the major challenges in [18F]-PET research is the installation of the weakly nucleophilic [18F]fluoride into a precursor molecule to access novel [18F]-tracers. Fluorinated nucleosides represent an important class of diagnostic probes for PET imaging as well as anticancer and antiviral therapeutic agents. However drug resistance still represents a major problem. The ProTide approach is a strategy to synthesize prodrugs of the nucleoside monophosphates which overcome their main resistance mechanisms. The challenge of the project is the [18F]-fluorination (hot fluorination) of ProTides which may be potential new PET imaging agents and could thus represent a model system to visualize pharmaceutical effects and bioactivation of ProTides directly in vivo. The pro-nucleotide multistep synthetic chemistry has been applied for the synthesis of ProTides. The [18F]-radiolabeling of the precursor molecules was performed in an Eckert & Ziegler automated synthetic Modular Lab placed into a shielded hot cell. The radioactive reaction mixtures were analyzed by radio HPLC, and radio TLC. Two different approaches have been followed to access two chemically distinct radiolabelled ProTides. The 3’-[18F]FLT ProTide was synthesised via a late stage [18F]fluorination of ad hoc synthesised precursor molecules (Figure 1). Figure 1: Radiochemical synthesis of 18F- FLT ProTides The 2’-[18F]FIAU ProTide was synthesised via an early stage [18F]fluorination approach (Figure 2). Figure 2: Radiochemical synthesis of 18F-FIAU ProTides These radiolabelled probes could provide evidence for the in vivo behaviour of this class of compounds by answering key questions about their metabolism and uptake directly. In addition, the project focused on the synthesis of two novel classes of non-radiolabelled fluorinated ProTides. A series of uridine based ProTides (FIAU ProTides) and a series of coumarin based FLT ProTides have been synthesised and evaluated for their antiviral activity and fluorescent properties respectively.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Pharmacy
Subjects: Q Science > Q Science (General)
Uncontrolled Keywords: Positron Emission Tomography, ProTides, Fluorine, 18Fluorine, Fluorinated nucleosides, Fluorination
Date of First Compliant Deposit: 20 March 2018
Last Modified: 20 Mar 2018 09:11
URI: http://orca-mwe.cf.ac.uk/id/eprint/109710

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