Metal carbohydrate conjugates for diagnostic and therapeutic applications

This thesis examines the use of carbohydrates to prepare targeted metal complexes as potential diagnostic and therapeutic agents. Carbohydrates are important molecules in living systems, thus highly developed pathways exist for their transport and utilization, and carbohydrate conjugates that take advantage of these pathways have a range of potential medical applications. Carbohydrate conjugates of relevant radioisotopes have value as diagnostic imaging and radiotherapy agents. Utilizing a number of radioisotopes, metal carbohydrate conjugates were prepared and evaluated as potential radiopharmaceuticals. Bidentate, tridentate and cyclopentadienyl ligands with pendant carbohydrates were studied with the [M(CO)3]+ (M = Re, 99mTc, 186Re) core; 99mTc is an optimal imaging radioisotope and 186Re is of interest for radiotherapy. The complexes of the tridentate ligands were typically more stable than were the complexes of the bidentate ligands. Biodistribution and planar scintigraphy imaging studies with the tridentate complexes showed tumour uptake, suggesting they may have potential as tumour imaging agents. One complex, a glucosamine conjugate with a cyclopentadienyl ligand, retained some biological recognition, as it was shown to be a competitive inhibitor of hexokinase, the first enzyme in glucose metabolism. Ga, In, Cu, and Co all have radioisotopes that can be used in nuclear medicine. Carbohydrate bearing bidentate ligands formed tris(ligand) complexes with Ga(III) and In(III), and bis(ligand) complexes with Cu(II) and Co(II). 67Ga and 64Cu were used in high yield radiolabelling procedures using these bidentate ligands, but the resulting complexes proved to be susceptible to ligand exchange with amino acids. Targeting the high glucose consumption of the parasite that causes malaria is a novel approach for developing anti-malarials. As well, ferrocene based complexes have shown efficacy in resistant strains of the parasite. Thus ferrocene-carbohydrate conjugates were prepared and examined as potential malaria therapeutics. Several of these complexes had moderate anti-malarial activity in in vitro studies, but their proposed ability to target the high glucose consumption of infected erythrocytes may result in higher efficacy in vivo.