New Gastrin Releasing Peptide Receptor-Directed [99mTc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation

We have previously reported on the gastrin releasing peptide receptor (GRPR) antagonist [99mTc]1, ([99mTc]­demobesin 1, 99mTc-[N4′-diglycolate-dPhe6,Leu-NHEt13]­BBN­(6–13)). [99mTc]1 has shown superior biological profile compared to analogous agonist-based 99mTc-radioligands. We herein present a small library of [99mTc]1 mimics generated after structural modifications in (a) the linker ([99mTc]2, [99mTc]3, [99mTc]4), (b) the peptide chain ([99mTc]5, [99mTc]6), and (c) the C-terminus ([99mTc]7 or [99mTc]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, [99mTc]1–[99mTc]6 exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [99mTc]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 [99mTc]1 (5.4 ± 0.7%ID/g at 24 h pi).