Date of Award

4-2010

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

Supervisor

John Fitzmaurice Valliant

Language

English

Abstract

This thesis demonstrates the versatility of the carborane cage by qsing a known carborane containing analogue of the amino acid phenylalanine, carborananylalanine (Car
5) as a novel platform for radio labelling targeting vectors with both 99mTc and 125I. Initial racemic synthesis of Car was undertaken based on a literature procedure. Optimization of the procedure yielded all key intermediates leading to closo-carboranylalanine which was obtained in 67% yield. A new method for cage degradation of Car 5 involving microwave heating in water to give the desired nido-Car 9 was developed such that the product could be isolated in quantitative yield where the only additional product was boric acid. The removal of boric acid was non-trivial but was ultimately achieved through conversion to the more volatile borate ester.

The synthesis of Re-Car 12 was achieved by microwave heating nido-Car 9 with [Re(CO)3(H2O)3]Br at 180∘C for 15 min in a microwave. The reaction produced multiple carborane products including the desired product 12, an amino acid rhenium chelate complex 15, and a di-rhenium complex 14. Conditions were altered to maximize the amount of the desired compound which was separated from impurities through semipreparative HPLC albeit in low yield (3%). Analysis of 12 by 1H nOe NMR experiments revealed that cage isomerization had occurred under the employed conditions resulting in the formation of the 2, 1, 8-cage isomer of 12.

The iodination of nido-Car was found to take place in high yield at room temperature with a reaction time of less than 10 minutes. When the stoichiometry was kept to a 1:1 ratio between 9 and I2 no other side products were observed and purification by semi-preparative HPLC gave pure I-Car 16 in 48% yield.

It was found that the radiolabelling of nido-Car with 99mTc proceeded with very few side products as compared to the cold rhenium standard (Re-Car 12). Variations of the labelling conditions (time, temperature and pH) resulted in a 45% percent conversion to the desired 99mTc_Car 13. The HPLC retention time of the 99mTc product correlated to the Re-Car 12 reference standard.

Radiolabelling of nido-Car with 125I using Iodogen® as an oxidant was fast, efficient and high yielding. It was found that under the standard labelling conditions, nido-Car would give high conversion (>95%) to 125I_Car 18 in less than 10 minutes at room temperature. Not only was 9 highly reactive towards radioiodination, but the resulting product was found to be remarkably stable with no signs of degradation up to two weeks.

A dilution study to examme the reactivity of 9 towards radioiodination was performed. At concentrations of 4.5 mM and 2.3 mM the conversion of 9 to 125I-Car 18 occurred in >95% conversion and 70% conversion occurred at a ligand concentration of 1.1 mM. A head-to-head experiment using equimolar amounts of tyrosine to nido-Car was also performed and found that 125I-Car was formed prefentially with an average percent conversion of 93%.

This work demonstrates that a versatile radiolabelling platform using carboranes can be developed. Because the ligand is a non-natural amino acid it can serve for preparing bioconjugates and targeted molecular imaging and therapy agents.

McMaster University Library


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