title: Impact of functionalized coligands on the pharmacokinetics of 99mTcIII '4+1' mixed-ligand complexes conjugated to bombesin.
abstract: Bombesins (BN) containing (99m)Tc '4+1' complexes may be useful to detect tumors expressing the gastrin-releasing peptide receptor (GRPR). Derivatives of the formula [(99m)Tc(NS(3)R)(L2-BN(st))] were synthesized, in which Tc(III) is coordinated by an isocyanide L2-BN(st) bearing the peptide (BN(st)=βAla-βAla-Gln-Trp-Ala-Val-Gly-His-Cha-Nle-NH(2)) and a tetradentate chelator NS(3)R. NS(3)R consists of 2,2',2″-nitrilotriethanethiol (NS(3)) bearing a crown ether (NS(3)crown), an aliphatic amine (NS(3)en) and a tricarboxylic acid (NS(3)(COOH)(3)). Non-radioactive Re compounds were prepared and analysed by electrospray ionization mass spectrometry. The structural similarity to the (99m)Tc conjugates was demonstrated by their identical HPLC elution profiles. The lipophilicity of [(99m)Tc(NS(3)R)(L2-BN(st))] decreased depending on the coligands NS(3)crown (log D(O/W), pH=7.4, 0.98 ± 0.11), NS(3)en (-0.49 ± 0.07) and NS(3)(COOH)(3) (-2.01 ± 0.09). Biodistribution in normal rats was characterized by an increasing kidney uptake and a decreasing uptake into the liver corresponding to the reduced lipophilicity of the conjugates. The pancreatic uptake expressed by the organ/blood ratio of standardized uptake values at 60 min p.i. in rats was 8.6 ± 1.2 for [(99m)Tc(NS(3)en)(L2-BN(st))] and higher compared to the other conjugates. The pancreas/liver ratio of the SUV at 60 min p.i. in rats was highest for [(99m)Tc(NS(3)(COOH)(3))(L2-BN(st))] at 8.4 ± 1.3. [(99m)Tc(NS(3)en)(L2-BN(st))] was further studied in tumor-bearing mice and its pancreas/blood and pancreas/liver ratios were lower, however the pancreas/kidney ratios were higher in mice compared to rats. The activity uptake of [(99m)Tc(NS(3)en)(L2-BN(st))] into the PC-3 tumor xenografts was low (%ID/g: 0.83 ± 0.18 at 60 min; SUV: 0.21 ± 0.05 at 60 min) but specific.
authors.affiliation: Institute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf, 01314 Dresden, Germany.
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Kunstler
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Ewa
authors.initials: E
authors.lastname: Gniazdowska
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Koźmiński
authors.forename: Martin
authors.initials: M
authors.lastname: Walther
authors.forename: Hans-Jurgen
authors.initials: HJ
authors.lastname: Pietzsch
mesh_terms: D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D003486:Cyanides / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D004355:Drug Stability; D005260:Female; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007553:Isotope Labeling; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000000981:diagnostic imaging; D010179:Pancreas / Q000000981:diagnostic imaging / Q000378:metabolism; D010446:Peptide Fragments; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D018004:Receptors, Bombesin / Q000378:metabolism; D012211:Rhenium / Q000737:chemistry; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D056831:Coordination Complexes; D003486:Cyanides; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018004:Receptors, Bombesin; C118536:bombesin (7-14); D012211:Rhenium; D013667:Technetium; D001839:Bombesin