Date of Award
Bachelor of Science (B.S.) in Chemistry and University Honors
Contrast media (Diagnostic imaging) -- Synthesis, Contrast-enhanced magnetic resonance imaging, Magnetic resonance imaging
The complex between the macrocyclic ligand DOTA and the metal gadolinium (Gd3+) has been used as the contrast agent for the MRI T1 weighed imaging. Mono substitution on the tetraaza ring of DOTA ligand results in the formation of the two distinct complexes that are regioisomers of each other and they have different contrast efficiency as well as stability. These regioisomers are only separated by HPLC. With two bulky substituents on the tetraaza ring, it is expected to increase the selectivity of what regioisomers will be formed for each di-substituting pattern since the conformation with the least steric hindrance will be favored most to maintain the stability of the ring structure. This will simplify the synthesis procedure by removing the separation of the different regioisomers. The contrast efficiency and stability of the complexes made from these new ligands will also need to be explored. Based on the special characteristics of the DOTA’s tetraaza ring, three di-substitution patterns will be studied are 2,8-S,S, 2,9-S,S, and 2,5-S,S. This paper’s goal is to report the synthesis progress of these three patterns. The synthesis includes four main stages: dibenzyl polypeptide chain, dibenzyl tetra amine chain, dibenzyl tetraaza cyclododecane, and dibenzyl DOTA. Cyclization in the third stage is crucial to control the di-substitution patterns. The identity of the product in each step was verified by using 1H-NMR and mass spectrometry. Pattern 2,9-S,S passed the first two stages and its dibenzyl tetraamine chain needs to be purified before entering the cyclization process. Pattern 2,8-S,S could not be built from the N terminal (after building the second peptide bonds, the intermediate product had solubility issues.) The first peptide bond for the pattern 2,5-S,S is still being built from the N terminal.
Nguyen, Chau V., "The Synthesis of Di-substituted DOTA Ligands for MRI Contrast Agents." (2019). University Honors Theses. Paper 754.