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).

1 Follower
36 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Affibody molecules constitute a class of small (7 kDa) scaffold proteins that can be engineered to have excellent tumor targeting properties. High reabsorption in kidneys complicates development of affibody molecules for radionuclide therapy. In this study, we evaluated the influence of the composition of cysteine-containing C-terminal peptide-based chelators on the biodistribution and renal retention of (188)Re-labeled anti-HER2 affibody molecules. Biodistribution of affibody molecules containing GGXC or GXGC peptide chelators (where X is G, S, E or K) was compared with biodistribution of a parental affibody molecule ZHER2:2395 having a KVDC peptide chelator. All constructs retained low picomolar affinity to HER2-expressing cells after labeling. The biodistribution of all (188)Re-labeled affibody molecules was in general comparable, with the main observed difference found in the uptake and retention of radioactivity in excretory organs. The (188)Re-ZHER2:V2 affibody molecule with a GGGC chelator provided the lowest uptake in all organs and tissues. The renal retention of (188)Re-ZHER2:V2 (3.1 ± 0.5 %ID/g at 4 h after injection) was 55-fold lower than retention of the parental (188)Re-ZHER2:2395 (172 ± 32 %ID/g). We show that engineering of cysteine-containing peptide-based chelators can be used for significant improvement of biodistribution of (188)Re-labeled scaffold proteins, particularly reduction of their uptake in excretory organs.
    Full-text · Article · Sep 2014 · European Journal of Medicinal Chemistry
  • [Show abstract] [Hide abstract]
    ABSTRACT: Solder interconnection technology is currently in need of alternatives to address environmental issues associated with lead (Pb) abatement, and elimination of fluxes and flux cleaning solvents, and technical challenges related to extending to fine pitch assembly. Electrically conducting adhesive technology is one of the alternatives being actively considered in this context. The most common conductive adhesive used today is an epoxy resin filled with fine silver particles. Silver particles provide electrical conduction, while epoxy provides adhesive bonding of the components to a substrate. This material has several limitations such as low electrical conductivity, low joint strength, increase in contact resistance upon thermal cycling, and silver migration. In order to overcome these limitations, a new formulation is proposed based on alternative Pb-free conducting filler powders and tailored polymer resins. This new material provides a metallurgical bonding as well as polymer adhesive bonding leading to an increase in joint strength and in electrical conductivity. Several potential applications of these adhesive materials such as glass-to-board connection in LCD packaging, SMT package assembly to PCB, and direct chip attachment to a high density card are discussed
    No preview · Conference Paper · Jun 1995
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxorhenium(V) complexes with '3+1' mixed ligands, [ReO(SSS)L], where SSS is eta(3)-(SCH2CH2SCH2CH2S), L = eta(1)-(C6H4COOH-4S), eta(1)-(C6H4CONHCH2COOEt-4-S), eta(1)-(C6H4CONHCH(CH3)COOEt-4-S), and eta(1)-(C6H4CONHCH(CH2Ph)COOEt-4-S), have been synthesized. These L ligands and [ReO(SSS)L] complexes were characterized by IR, H-1 NMR, C-13 NMR, and MAS spectrometers. Molecular structure of [ReO(SSS) {eta(1)-(C6H4COOH-4-S)}] complex was determined to be a distorted square pyramidal by single crystal X-ray analytical method. (c) 2007 Elsevier B.V. All rights reserved.
    Full-text · Article · Jun 2007 · Inorganica Chimica Acta
Show more