Hybrid Bombesin Analogues: Combining an Agonist and an Antagonist in Defined Distances for Optimized Tumor Targeting

Radiolabeled hybrid ligands with defined distances between an agonist and an antagonist for the gastrin-releasing peptide receptor were found to have excellent tumor-targeting properties. Oligoprolines served as rigid scaffolds that allowed for tailoring distances of 10, 20, and 30 Å between the recognition elements. In vitro and in vivo studies revealed that the hybrid ligand with a distance of 20 Å between the recognition elements exhibits the highest yet observed tumor cell uptake and retention time in prostate cancer cells

Additional file 2 of CUDC-907, a dual PI3K/histone deacetylase inhibitor, increases meta-iodobenzylguanidine uptake (123/131I-mIBG) in vitro and in vivo: a promising candidate for advancing theranostics in neuroendocrine tumors

Additional file 2. Additional data

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]<b>1</b>, ([^99mTc]­demobesin 1, ^99mTc-[N₄′-diglycolate-dPhe⁶,Leu-NHEt¹³]­BBN­(6–13)). [^99mTc]<b>1</b> has shown superior biological profile compared to analogous agonist-based ^99mTc-radioligands. We herein present a small library of [^99mTc]<b>1</b> mimics generated after structural modifications in (a) the linker ([^99mTc]<b>2</b>, [^99mTc]<b>3</b>, [^99mTc]<b>4</b>), (b) the peptide chain ([^99mTc]<b>5</b>, [^99mTc]<b>6</b>), and (c) the C-terminus ([^99mTc]<b>7</b> or [^99mTc]<b>8</b>). 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 <b>4</b> and <b>8</b> behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [^99mTc]<b>1</b>–[^99mTc]<b>6</b> exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [^99mTc]<b>4</b> 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]<b>1</b> (5.4 ± 0.7%ID/g at 24 h pi)

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]<b>1</b>, ([^99mTc]­demobesin 1, ^99mTc-[N₄′-diglycolate-dPhe⁶,Leu-NHEt¹³]­BBN­(6–13)). [^99mTc]<b>1</b> has shown superior biological profile compared to analogous agonist-based ^99mTc-radioligands. We herein present a small library of [^99mTc]<b>1</b> mimics generated after structural modifications in (a) the linker ([^99mTc]<b>2</b>, [^99mTc]<b>3</b>, [^99mTc]<b>4</b>), (b) the peptide chain ([^99mTc]<b>5</b>, [^99mTc]<b>6</b>), and (c) the C-terminus ([^99mTc]<b>7</b> or [^99mTc]<b>8</b>). 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 <b>4</b> and <b>8</b> behaved as potent GRPR antagonists in a functional internalization assay. In mice bearing PC-3 tumors, [^99mTc]<b>1</b>–[^99mTc]<b>6</b> exhibited GRPR-specific tumor uptake, rapidly clearing from normal tissues. [^99mTc]<b>4</b> 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]<b>1</b> (5.4 ± 0.7%ID/g at 24 h pi)