Rhenium cyclized alpha-MSH analogs, somatostatin analogs and T-antigen avid peptides as imaging and therapeutic agents for tumor targeting

Utilization of biologically active peptides as a radionuclide delivery system for cancer detection and treatment has proven to be an effective approach in recent research. Three types of peptides, rhenium cyclized α-melanocyte stimulating hormone (α-MSH) analogs, somatostatin analogs and T-antigen avid peptides have been synthesized and evaluated as potential peptide radiopharmaceuticals for cancer targeting in this thesis.; Rhenium cyclized α-MSH is a novel metallopeptide that exhibits high melanoma uptake and retention and quick clearance from normal tissue. To expand its ability for targeting with a wider variety of radionuclides for melanoma imaging and therapy purposes, several rhenium cyclized α-MSH derivatives were synthesized, radiolabeled with different radionuclides (e.g., In-111, I-125), and evaluated in vitro and in vivo . Among these analogs, 111In-DOTA-ReCCMSH(Arg 11) showed high melanoma uptake and low background activity, which justified its radiolabeling with metallic radionuclides for further investigation as potential imaging and therapeutic radiopharmaceuticals. Ac-d-Lys-( 125I-IBA)-ReCCMSH(Arg11) exhibited remarkably high tumor uptake, enhanced cellular retention and low background in normal tissues. These observations demonstrated that Ac-d-Lys-ReCCMSH(Arg11) is an excellent candidate for the development of radiohalogenated peptides for melanoma radioimaging/radiotherapy.; Since the incorporation of “unnatural” rhenium or technetium into peptides generated metal cyclized peptides with favorable properties, several rhenium/technetium cyclized somatostatin analogs were designed to target receptors on somatostatin receptor positive tumors. 1D and 2D NMR (TOCSY, ROESY, and NOESY) and mass spectrometry studies were used to determine the metal coordination sites in the complexes using nonradioactive rhenium. The results demonstrated that rhenium core in ReOTS1-pk1 were coordinated by three thiolate sulfurs from Cys5, 6, 12 and one amide nitrogen from Cys6. Molecular dynamic studies using computer modeling predicted these analogs would possess high binding affinities with somatostatin receptors and the stability of these complexes would have the relative ranking of TcTS1 > TcTS2 > TcTS3 > TcTS4, which was verified by stability studies. These results illustrated that these metalated analogs were potential somatostatin receptor-positive tumor targeting peptides.; T-antigens present on many types of tumor cells. Several T-antigen specific peptides were derivatized with the amino acid sequence Ac-CGC(G) for labeling with technetium-99m. The peptides were readily labeled in high yield, and the radiolabeled peptides possessed good stability. In vivo biodistribution studies demonstrated that the aromatic rich peptides had high liver uptake and slow clearance, while the modified shorter peptides exhibited lower liver uptake and an improved biodistribution profile.