TECHNETIUM-99M CARBONYL COMPLEXES AND CONJUGATION STRATEGIES FOR TARGETED MOLECULAR IMAGING

Benjamin B. Kasten

99mTc is the most widely used diagnostic radionuclide in nuclear medicine. Targeted molecular imaging with 99mTc involves attaching the metal to a targeting vector molecule that interacts with specific biomarkers in diseased tissues, thus allowing non-invasive detection and assessment of the disease. It is widely known that the properties of the metal complex and method of vector functionalization significantly affect the performance of the resulting radiopharmaceutical. There is continued interest in developing complexation and conjugation strategies for constructing clinically relevant targeted molecular imaging agents with 99mTc. The organometallic fac-[99mTcI(CO)₃]+ core represents a versatile synthon for these applications due to its reliable formation, stability, and ability to efficiently coordinate a wide variety of ligands. This dissertation presents novel, widely applicable strategies to generate metal complexes and biomolecule conjugates of fac-[99mTcI(CO)₃]+ for targeted molecular imaging applications. The first study examined a functionalized cysteine chelate for coordinating the fac-[MI(CO)₃]+ (M = Re, 99mTc) core and incorporated the ligand into an α-melanocyte stimulating hormone peptide. Complexation studies with model ligands and the functionalized peptide followed by in vitro and in vivo analyses of the peptide complex using murine melanoma models established the validity of the chelation strategy for labeling peptides with fac-[MI(CO)₃]+. The second study utilized a hydrophilic, carboxylate-functionalized 2,2´-dipicolylamine (DPA) chelate for biomolecule conjugations via Cu(I) catalyzed azide/alkyne cycloaddition (click) reactions. An azide-functionalized cysteine in a melanoma-targeting peptide was clicked to carboxylated or non-carboxylated alkyne-functionalized DPA chelates and fac-[MI(CO)₃]+ complexes. In vitro and in vivo murine melanoma models were used to compare the influence of the different DPA complexes on the targeting affinity and biodistribution behavior of the peptides. The results confirmed the utility of the novel, hydrophilic complex for generating targeted peptide conjugates via click chemistry. The third study developed isothiocyanate-functionalized DPA ligands and fac-[MI(CO)₃]+ complexes for conjugation reactions with amine-containing biomolecules. Utilizing lysine as a preliminary model for peptide-based biomolecules established the proof of concept that the isothiocyanate derivatives could be used to prepare targeted radiopharmaceuticals. Finally, strategies utilizing phosphine ligands with fac-[MI(CO)₃]+ complexes were developed and showed potential for use with targeting agents in future endeavors.

TECHNETIUM-99M CARBONYL COMPLEXES AND CONJUGATION STRATEGIES FOR TARGETED MOLECULAR IMAGING

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