We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [Tc]1, ([Tc]demobesin 1, Tc-[N'-diglycolate-dPhe,Leu-NHEt]BBN(6-13)). [Tc]1 has shown superior biological profile compared to analogous agonist-based Tc-radioligands. We herein present a small library of [Tc]1 mimics generated after structural modifications in (a) the linker ([Tc]2, [Tc]3, [Tc]4), (b) the peptide chain ([Tc]5, [Tc]6), and (c) the C-terminus ([Tc]7 or [Tc]8). The effects of above modifications on the biological properties of analogs were studied in PC-3 cells and tumor-bearing SCID mice. All analogs showed subnanomolar affinity for the human GRPR, while most receptor-affine 4 and 8 behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [Tc]1-[Tc]6 exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [Tc]4 displayed the highest tumor uptake (28.8 ± 4.1%ID/g at 1 h pi), which remained high even after 24 h pi (16.3 ± 1.8%ID/g), well surpassing that of [Tc]1 (5.4 ± 0.7%ID/g at 24 h pi).
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