Design, synthesis, and biological evaluation of an antagonist-bombesin analogue as targeting vector

The gastrin releasing peptide receptor (GRP-R) is overexpressed on a number of tumors and cancer cell lines including pancreas, prostate, breast, gastrointestinal, and small cell lung cancer (SCLC). Radiolabeled bombesin (BBN) analogues have exhibited high binding affinity and specificity to the GRP-R. A bombesin analogue with an antagonist targeting vector at the C-terminus, DOTA-aminohexanoyl-[D-Phe⁶, Leu-NHCH₂CH₂CH ₃¹³, des Met¹⁴] BBN[6-14] (1, "Bomproamide"), has been synthesized and displays high binding affinity (IC₅₀ = 1-36 ± 0.09 nM) against ¹²⁵I- Tyr⁴-BBN in in vitro competitive assays using PC-3 cells. Maximum internalization of ¹¹¹In-1 reached 14% in PC-3 cells after 45 min of incubation. Rapid (0.25 h PI) and high (12.21 ± 3.2%ID/g) pancreatic uptake of ¹¹¹In-1 was observed in healthy CF-1 mice, and 90% of the activity was blocked by coinjection of 100 μg of BBN. Rapid (0.25 h PI) and high uptake (6.90 ± 1.06%ID/g) was observed in PC-3 prostate cancer xenografts in SCID mice, as well as visualized clearly in a SPECT/CT study. These results support the use of a bombesin construct with an antagonist C-terminal vector as a candidate of choice for specific in vivo imaging of tumors overexpressing GRP-receptors.