Date of Award
Master of Science (MS)
John Fitzmaurice Valliant
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.
Gullon, Teri Janet, "The Preparation of Metallocarborane and Iodinated Carborane Amjno Acid Analogues for Molecular Imaging and Therapy" (2010). Open Access Dissertations and Theses. Paper 4493.
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