TECHNETIUM-99M CARBONYL COMPLEXES AND NEW LIGAND DEVELOPMENT FOR TARGETED RADIOPHARMACEUTICALS

Thomas Robert Hayes

99mTc is the primary radioisotope used for diagnostic imaging in nuclear medicine. Targeted imaging with 99mTc involves the attachment of the metal using a bifunctional chelator to a biologically active targeting vector. Attachment of the metal to the targeting vector, however, can have detrimental effects on the biodistribution and targeting properties and directly affect the performance of the radiopharmaceutical. To address this, new ligands and conjugation methods continue to be developed to affect the pharmacokinetics of the radiopharmaceuticals. The organometallic fac-[MI(CO)3]+ (M = Re, 99mTc) core represents a versatile synthon for the development of new targeted radiopharmaceuticals. This dissertation presents novel strategies for the complexation of the fac-[MI(CO)3]+ core as well as structure activity studies for the further development of pyridine-based ligand systems. The first two studies examine new bidentate ligands for fac-[MI(CO)3]+, using either 2+1+1 or 2+1 labeling strategies, using bidentate and monodentate ligands, to examine stability and feasibility for their use as a radiopharmaceutical platform. The third study examines the effect of substitution on pyridine based ligands. Many of the common chelators for fac-[MI(CO)3]+ contain one or more pyridine ligands. A 2+1 labeling strategy was used with picolinic acid to examine the effect of substitution on the metal complexes. Substitution on the pyridine ring can be used to modify lipophilicity, stability and other pharmacokinetic properties such as biodistribution and excretion pathways. It was shown that labeling efficiency and stability were directly associated with pyridine pKa. The fourth study investigated complex charge and aromatic nitrogen donor type on complex formation and stability. Both cationic and neutral systems were investigated with pyridine and imidazole based ligands. This study indicates that cationic complexes with fac-[MI(CO)3]+ will likely have the highest stability in vivo over similar neutral complexes. Finally, a novel urea system was developed with the 2,2’-dipicolylamine chelator. Functionalization of the central amine of the chelator with a phenyl urea gives a ligand for fac-[MI(CO)3]+ where metal coordination leads to a controlled release of a DPA complex. Application of this to a solid phase would allow for the creation of high specific activity radiopharmaceuticals with minimal purification.

TECHNETIUM-99M CARBONYL COMPLEXES AND NEW LIGAND DEVELOPMENT FOR TARGETED RADIOPHARMACEUTICALS

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