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

Abstract

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).

New Monodentate Amidine Superbasic Ligands with a Single Configuration infac-[Re(CO)3(5,5′- or 6,6′-Me2bipyridine)(amidine)]BF4Complexes

“…2,10–11 At present, great interest surrounds the concept of combining 99m Tc and 186/188 Re with biomolecules in order to produce selective targeting agents. 5–6,11–17 fac -[Re I (CO) 3 L] n complexes prepared with natural-abundance rhenium are excellent models for the short-lived fac -[M I (CO) 3 L] n radiopharmaceuticals and are almost non-radioactive. Thus, the investigation of fac -[Re I (CO) 3 L] n complexes both aids in interpreting the chemistry of the radiopharmaceuticals and offers the potential for the discovery of new chemistry, some of which could be applied to radiopharmaceutical development.…”

Evaluation of the Therapeutic and Diagnostic Effects of PEGylated Liposome–Embedded 188Re on Human Non–Small Cell Lung Cancer Using an Orthotopic Small-Animal Model

“…Recently, 188 Re has been embedded in nanoscale liposomes via N,N-bis(2-mercaptoethyl)-N9,N9-diethylethylenediamine (BMEDA) chelator and proved to be ideal for targeting in the local and lung metastatic colorectal cancer animal model (15). Additionally, conjugation of 188 Re or 99m Tc to the somatostatin receptor-binding peptide analog P2045 has been demonstrated to be a potent radiopharmaceutical for lung cancer therapy and diagnosis, and it has entered phase I clinical trials (16)(17)(18). Whether 188 Re conjugated to nanoscale liposomes is also beneficial for the treatment of human NSCLC would be of interest to investigate further.…”

188Re-ZHER2:V2, a Promising Affibody-Based Targeting Agent Against HER2-Expressing Tumors: Preclinical Assessment

“…We expected that substitution of 99m Tc for 188 Re in Affibody molecules might provide a conjugate with a high tumor uptake and low renal retention. However, the chemical properties of rhenium and technetium are similar but not identical, and biodistribution of 99m Tc-and 188 Re-labeled peptides can be different (24,25). Therefore, an evaluation of 188 Re-labeled Z HER2:V2 was necessary.…”