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Author

Neil Vasdev

Date of Award

3-2003

Degree Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Supervisor

Professor R. V. Chirakal

Co-Supervisor

Professor G. J. Schrobilgen

Abstract

Previously, the fate of 5-fluoro-L-DOPA in the human brian was unknown because an efficient method for the synthesis of [18F]5-fluoro-L-DOPA in mCi quantities was not available. In the present work, a method for the synthesis of [18F]5-fluoro-L-DOPA in mCi quantities was developed by studying the reactivity and selectivity of fluorine during the electrophilic fluorination of L-DOPA in acidic solvents. As a result of this work, the present study has reported the first clinical study, using positron emission tomography (PET), that compared the in vivo behaviour of [18F]2-, [18F]5- and [18F]6-fluoro-L-DOPA, in the living human brain.

The site-specific fluorination method developed in the present work was extended to develop a high-yield synthesis of [18F]3-fluoro-L-α-methyltyrosine, which is a tumour imaging agent. Direct fluorination of L-α-methyltyrosine with [18F]F2 in HF solvent produced the 3-fluoro isomer as the major product in 30% radiochemical yield (RCY) with respect to [18F]F2, the highest RCY to date. These studies also revealed that a previous report had incorrectly characterized [18F]3,5-difluoro-L-α-methyltyrosine as [18F]2-fluoro-L-α-methyltyrosine. This methodology was further extended to develop a new PET tracer, [18F]5-fluoro-3-nitro-L-tyrosine, in order to trace "reactive nitrogen species", which are responsible for tissue damage in vivo.

A recent study has claimed that XeF2 exchanges with [2,2,2-crypt-M][18F] (M = K or Cs) to produce [18F]XeF2 at room temperature in CH2Cl2 solvent and that exchange between F and XeF2 cannot occur in CH3CN solvent. Contrary to previous work, the present study showed that both XeF2 and F react with CH2Cl2 at room temperature and that XeF2 fluorinates 2,2,2-crypt under rigorously anhydrous conditions. The major products resulting from these reactions include several hydrochlorofluorocarbons and large amounts of HF and HF2. Thus, the exchange between XeF2 and 18F reported in the prior work arises from exchange between XeF2 and HF/HF2, and does not involve fluoride ion. Furthermore, two-dimensional EXSY and single selective inversion NMR spectroscopic studies in the present work have shown that anhydrous [N(CH3)4][F] exchanges with XeF2 in CH3CN solvent. The exchange between XeF2 and F is postulated to proceed by the formation of the trifluoroxenate(II) anion, XeF3, a novel VSEPR system (i.e., the first AX3E3 arrangement), as the exchange intermediate.

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