Impact of functionalized coligands on the pharmacokinetics of 99mTcIII '4+1' mixed-ligand complexes conjugated to bombesin.

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.