Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with Tb and Lu: A Comparative Study.

To elucidate potential benefits of the Auger-electron-emitting radionuclide Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) and AMTG (α-Me-Trp-RM2), each labeled with both Lu and Tb. Tb/Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice. Gastrin-releasing peptide receptor affinity was high for all compounds (half-maximal inhibitory concentration [nM]: [Tb]Tb-RM2, 2.46 ± 0.16; [Tb]Tb-AMTG, 2.16 ± 0.09; [Lu]Lu-RM2, 3.45 ± 0.18; [Lu]Lu-AMTG, 3.04 ± 0.08), and 75%-84% of cell-associated activity was receptor-bound. In vivo, both AMTG analogs displayed distinctly higher stability (30 min after injection) and noticeably higher tumor retention than their RM2 counterparts. On the basis of preclinical results, [Tb]Tb-/[Lu]Lu-AMTG might reveal a higher therapeutic efficacy than [Tb]Tb-/[Lu]Lu-RM2, particularly [Tb]Tb-AMTG because of additional Auger-electron emissions at the cell membrane level.