Impact of functionalized coligands on the pharmacokinetics of 99mTc(III) ‘4 + 1’ mixed-ligand complexes conjugated to bombesin

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.

Graphical abstractNovel bombesin derivatives containing a 99mTc ‘4 + 1’ mixed-ligand complex coupled to βAla-βAla-[Cha13, Nle14]bombesin(7–14) showed different biodistribution data in rats and mice depending from complex pendant modifying units and were assessed by in vivo metabolism studies.Figure optionsDownload full-size imageDownload as PowerPoint slide