Acyclic chelates for imaging with radiometals

This thesis investigates acyclic chelates containing pyridine, carboxylate and amino groups and their fast and efficient and stable coordination of the (radio-)metals ⁹⁹mTc, Re, Cu, ⁶⁴Cu, Ga, ⁶⁷/⁶⁸Ga. The radiometals mentioned are all of significant interest for SPECT (single photon emission computed tomography) and PET (positron emission tomography) imaging, two of the most important non-invasive diagnostic tools in the clinic. The design, synthesis, radiolabelling, evaluation of stability, and in vivo investigation are presented for three variably charged, novel, short C₈ chain derivatized chelates for the [M(CO)₃]+ core (M = ⁹⁹mTc or Re). Distinct localization of these small amphiphilic molecules in vivo was studied via biodistribution and imaging and was found to be dependent on the charge of the polar moiety. In an attempt to identify a universal chelate applicable to the [M(CO)₃]+ core and ⁶⁴Cu, the synthesis of the dipin bifunctional chelate system, capable of fast coordination of Cu, its radionuclide ⁶⁴Cu, as well as the [M(CO)₃]+ core (M = ⁹⁹mTc, Re) is described. The versatility of the dipin ligand system is based on its ability to adopt a variety of binding modes, tridentate when protected, tetradentate when deprotected. Based on this small, tetradentate scaffold, a series of acyclic chelates with varying bite angle and denticity were synthesized and screened for their ability to coordinate radioisotopes of Ga and Cu under mild conditions within a short period of time. It was found that the linear N₄O₂ chelate H₂dedpa coordinates ⁶⁷/⁶⁸Ga quantitatively to form [⁶⁷Ga(dedpa)]+ after 10 min at room temperature with exceptional kinetic inertness towards human apo-transferrin. The corresponding ⁶⁴Cu complex maintains inertness against serum proteins within 2 h, but shows 23 % transchelation to serum proteins after 24 h. Both potential small molecule perfusion agents, as well as peptide conjugated versions as applications of the H2dedpa scaffold are reported. Both types of derivatives maintained the labelling and radiolabelled complex (⁶⁷/⁶⁸Ga and ⁶⁴Cu) stability properties found with the non-derivatized versions, further indicating the H₂dedpa scaffold is a useful platform for the development of clinically applicable radiopharmaceuticals.Science, Faculty ofChemistry, Department ofGraduat