Impact of functionalized coligands on the pharmacokinetics of 99mTcIII '4+1' mixed-ligand complexes conjugated to bombesin |
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Authors: | Kunstler Jens-Uwe Bergmann Ralf Gniazdowska Ewa Ko?miński Przemyslaw Walther Martin Pietzsch Hans-Jurgen |
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Institution: | aInstitute of Radiopharmacy, Forschungszentrum Dresden-Rossendorf, 01314 Dresden, Germany;bInstitute of Nuclear Chemistry and Technology, 03-195 Warsaw, Poland |
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Abstract: | Bombesins (BN) containing 99mTc ‘4 + 1’ complexes may be useful to detect tumors expressing the gastrin-releasing peptide receptor (GRPR). Derivatives of the formula 99mTc(NS3R)(L2-BNst)] were synthesized, in which Tc(III) is coordinated by an isocyanide L2-BNst bearing the peptide (BNst = βAla-βAla-Gln-Trp-Ala-Val-Gly-His-Cha-Nle-NH2) and a tetradentate chelator NS3R. NS3R consists of 2,2′,2″-nitrilotriethanethiol (NS3) bearing a crown ether (NS3crown), an aliphatic amine (NS3en) and a tricarboxylic acid (NS3(COOH)3). Non-radioactive Re compounds were prepared and analysed by electrospray ionization mass spectrometry. The structural similarity to the 99mTc conjugates was demonstrated by their identical HPLC elution profiles. The lipophilicity of 99mTc(NS3R)(L2-BNst)] decreased depending on the coligands NS3crown (log DO/W, pH = 7.4, 0.98 ± 0.11), NS3en (− 0.49 ± 0.07) and NS3(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 99mTc(NS3en)(L2-BNst)] and higher compared to the other conjugates. The pancreas/liver ratio of the SUV at 60 min p.i. in rats was highest for 99mTc(NS3(COOH)3)(L2-BNst)] at 8.4 ± 1.3. 99mTc(NS3en)(L2-BNst)] 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 99mTc(NS3en)(L2-BNst)] 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. |
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Keywords: | Technetium &lsquo 4 + 1&rsquo mixed-ligand complex Peptide Bombesin Metabolism |
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