Somatostatin Receptor-Binding Peptides Suitable for Tumor Radiotherapy with Re-188 or Re-186. Chemistry and Initial Biological Studies

Berlin-Chemie AG, Berlín, Berlin, Germany
Journal of Medicinal Chemistry (Impact Factor: 5.45). 03/2007; 50(6):1354-64. DOI: 10.1021/jm061290i
Source: PubMed


Somatostatin derivative peptides previously designed for radiodiagnostic purposes (99mTc P829 or 99mTc depreotide) were reoptimized for radiotherapy of tumors with rhenium radioisotopes. An optimized pharmacophore peptide P1839 was derived by in vitro binding affinity assay to AR42J rat pancreatic tumor cell membranes. Peptides with chelating domains and their oxorhenium(V) complexes were tested in vitro for binding to NCI H69 human SCLC tumor membranes. Further optimization entailed radiolabeling with 99mTc and biodistribution in an AR42J xenograft mouse model. Kidney uptake was decreased substantially by removing positively charged residues. Neutral N3S diamide amine thiol chelators with no adjacent positive charges had the best overall properties. Substituting an aromatic amino acid into the chelator approximately doubled the tumor uptake. The final optimized peptide P2045 (39) radiolabeled with 99mTc exhibited increased tumor uptake ( approximately 25 %ID/g at 1.5 h), lower kidney uptake ( approximately 4.8 %ID/g at 1.5 h), and extensive urinary excretion (59 %ID at 1.5 h). Finally, comparison biodistribution studies between 99mTc and 188Re (39) showed a good correlation between the two metal complexes and demonstrated prolonged tumor retention (> or =24 h).

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    • "This is essential, as our previous studies have demonstrated that the position of the chelators noticeably influences the biodistribution and targeting properties of 99m Tclabeled affibody molecules [32]. Generally, labeling with rhenium requires much higher concentration of reducing agents than labeling with technetium, and thus harsher labeling conditions [41]. These conditions are generally non-compatible with proteins that are dependent on disulfide bonds, such as antibodies and antibody fragments. "
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