by Stephanie Rathmann

Institution: McMaster University
Degree: MSc
Year: 2014
Record ID: 2025644
Full text PDF: http://hdl.handle.net/11375/16046


This thesis describes the synthesis, characterization, and biological testing of iodinated probes derived from halogenated triazoles, and the effect of substituents on the clearance and tumour to non-target ratios in murine models of melanoma. Following the preparation of a small library of stannylated candidates biodistribution studies for the corresponding radioiodinated probes were performed in C57Bl/6 mice bearing B16F1tumours. Among the compounds tested an iodinated triazole containing a piperidine and phenyl moiety, 125I-7g, showed the most promising results with high tumour to liver and eye to liver ratios (27 and 81 respectively) at 24 hours. SPECT/CT imaging was consistent and showed excellent tumour visualization with a very high signal to noise ratio, which was attributed to effective clearance of the 1,4 triazole core. As the most promising candidate 125I-7g offers a platform from which to develop melanin specific radiopharmaceutical with optimal clearance and tumour to non-target ratios. Using the results from the SAR study, the lead constructs were the basis for preparing second generation agents using antibody recruiting, bioorthogonal targeting and dendrimer platforms. A small molecule, antibody recruiting agent was synthesized, specific to melanoma, a scaffold previously shown successful with prostate cancer. A one pot click reaction was performed between an azide functionalized with the targeting vector, and an alkyne fuctionalized with a PEG-dinitrophenyl moiety. The reaction produced an iodinated triazole in 50% yield, which was used as a non-radioactive standard. The corresponding 125I derivative was also synthesized through a one pot click reaction, and isolated in 36% radiochemical yield with greater than 95% radiochemical purity. Unfortunately biodistribution studies showed limited uptake in the tumour (<1 %ID/g) at 24 hours. As an alternative to active targeting of melanoma, the BZA core was functionalized with a trans-cyclooctene (TCO) group, which is known to undergo a bioorthogonal click reaction with tetrazines in vivo. The TCO derivative was synthesized in 60% overall yield and administered to C57Bl/6 animal model prior to injection of a previously reported iodinated tetrazine. The data showed higher uptake in the tumour and the eyes, 0.7 and 6%ID/g respectively, when compared to the control group, 0.1 and 0.8 %ID/g respectively. These initial results indicate that the pretargeting approach holds significant promise in developing an effective approach to imaging and treating melanoma using medical isotopes. In an attempt to improve tumour uptake an aminobenzyl piperidine targeting vector, which was used to prepare compound 7g, was linked to a poly (2,2-bis(hydroxymethyl)-propanoic acid) (PMPA) generation one dendrimer through carbamate linkages. The product was isolated in 28% percent yield, and subsequently deprotected and combined with a stannylated triazole in 27% yield. The stannylated derivative was treated with Na125I and iodogen to give the radiolabelled compound in 19% RCY.…