Comparison of biological properties of [177Lu]Lu-ProBOMB1 and [177Lu]Lu-NeoBOMB1 for GRPR targeting

The gastrin-releasing peptide receptor (GRPR) is overexpressed in prostate cancer and other solid malignancies. Following up on our work on [Ga-68]Ga-ProBOMB1 that had better imaging characteristics than [Ga-68]Ga-NeoBOMB1, we investigated the effects of substituting Ga-68 for Lu-177 to determine if the resulting radiopharmaceuticals could be used with a therapeutic aim. We radiolabeled the bombesin antagonist ProBOMB1 (DOTA-pABzA-DIG-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-psi-Pro-NH2) with lutetium-177 and compared it with [Lu-177]Lu-NeoBOMB1 (obtained in 54.2 +/- 16.5% isolated radiochemical yield with >96% radiochemical purity and 440.8 +/- 165.1 GBq/mu mol molar activity) for GRPR targeting. Lu-NeoBOMB1 had better binding affinity for GRPR than Lu-ProBOMB1 (K-i values: 2.26 +/- 0.24 and 30.2 +/- 3.23nM). [Lu-177]Lu-ProBOMB1 was obtained in 53.7 +/- 5.4% decay-corrected radiochemical yield with 444.2 +/- 193.2 GBq/mu mol molar activity and >95% radiochemical purity. In PC-3 prostate cancer xenograft mice, tumor uptake of [Lu-177]Lu-ProBOMB1 was 3.38 +/- 1.00, 1.32 +/- 0.24, and 0.31 +/- 0.04%ID/g at 1, 4, and 24 hours pi. However, the uptake in tumor was lower than [Lu-177]Lu-NeoBOMB1 at all time points. [Lu-177]Lu-ProBOMB1 was inferior to [Lu-177]Lu-NeoBOMB1, which had better therapeutic index for the organs receiving the highest doses.