Influence of different chelators on the radiochemical properties of a 68-Gallium labelled bombesin analogue

The radiolabelled bombesin analogue AMBA shows high potential for diagnosis and treatment of prostate and breast cancer, but the influence of different chelators, which differ in terms of radiochemical reactivity and stability, have not been explored so far. In order to find the best suitable chelator for labelling of AMBA, we synthesized AMBA analogues linked to the most commonly used chelators DOTA, NOTA and NODAGA and compared their reactivity and stability after labelling with 68-Gallium. Methods: For the synthesis of DO3A-, NO2A- and NODAGA-AMBA, a solid-phase synthesis approach was used. The influence of concentration, pH and temperature on the radiolabelling was analysed. The in vitro stability of all complexes in saline, human serum, human whole blood and against transchelation and transmetallation was analysed. Results: The peptides were synthesised in high yield and purity. Purity and identity of products and impurities were confirmed using UHPLC coupled to ESI-MS. Radiolabelling of these peptides was optimal at elevated temperature, although room temperature labelling was reported previously for NOTA and NODAGA chelators. The highest reactivity was observed for NODAGA-AMBA. On preparation of NO2A-AMBA, the formation of a by-product was detected with HPLC. More detailed analysis revealed the formation of an isomer with the same mass to charge ratio which led to the conclusion that a coordination isomer was formed. All complexes showed high stability in saline, human serum or when challenged with DTPA, transferrin and varying metals (Fe3+, Cu2+, Zn2+). Conversely, the stability in human blood was low, and varying metabolites were detected and identified by ESI-MS. Conclusion: All three precursors are available in high yields suitable for routine production. NODAGA-AMBA showed the most favoured features when labelled with 68-gallium, but a further comparison in vivo should be performed in order to confirm the superior features found in vitro. (C) 2014 Elsevier Inc. All rights reserved.