3 research outputs found
Radiometal-Dependent Biological Profile of the Radiolabeled Gastrin-Releasing Peptide Receptor Antagonist SB3 in Cancer Theranostics: Metabolic and Biodistribution Patterns Defined by Neprilysin
Recent advances in
oncology involve the use of diagnostic/therapeutic
radionuclide-carrier pairs that target cancer cells, offering exciting
opportunities for personalized patient treatment. Theranostic gastrin-releasing
peptide receptor (GRPR)-directed radiopeptides have been proposed
for the management of GRPR-expressing prostate and breast cancers.
We have recently introduced the PET tracer <sup>68</sup>Ga-SB3 (SB3,
DOTA-<i>p</i>-aminomethylaniline-diglycolic acid-DPhe-Gln-Trp-Ala-Val-Gly-His-Leu-NHEt),
a receptor-radioantagonist that enables the visualization of GRPR-positive
lesions in humans. Aiming to fully assess the theranostic potential
of SB3, we herein report on the impact of switching <sup>68</sup>Ga
to <sup>111</sup>In/<sup>177</sup>Lu-label on the biological properties
of resulting radiopeptides. Notably, the bioavailability of <sup>111</sup>In/<sup>177</sup>Lu-SB3 in mice drastically deteriorated compared
with metabolically robust <sup>68</sup>Ga-SB3, and as a result led
to poorer <sup>111</sup>In/<sup>177</sup>Lu-SB3 uptake in GRPR-positive
PC-3 xenografts. The peptide cleavage sites were identified by chromatographic
comparison of blood samples from mice intravenously receiving <sup>111</sup>In/<sup>177</sup>Lu-SB3 with each of newly synthesized <sup>111</sup>In/<sup>177</sup>Lu-SB3-fragments. Coinjection of the radioconjugates
with the neprilysin (NEP)-inhibitor phosphoramidon led to full stabilization
of <sup>111</sup>In/<sup>177</sup>Lu-SB3 in peripheral mouse blood
and resulted in markedly enhanced radiolabel uptake in the PC-3 tumors.
In conclusion, in situ NEP-inhibition led to indistinguishable <sup>68</sup>Ga/<sup>111</sup>In/<sup>177</sup>Lu-SB3 profiles in mice
emphasizing the theranostic prospects of SB3 for clinical use
New Gastrin Releasing Peptide Receptor-Directed [<sup>99m</sup>Tc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation
We have previously reported on the
gastrin releasing peptide receptor (GRPR) antagonist [<sup>99m</sup>Tc]<b>1</b>, ([<sup>99m</sup>Tc]Âdemobesin 1, <sup>99m</sup>Tc-[N<sub>4</sub>′-diglycolate-dPhe<sup>6</sup>,Leu-NHEt<sup>13</sup>]ÂBBNÂ(6–13)). [<sup>99m</sup>Tc]<b>1</b> has
shown superior biological profile compared to analogous agonist-based <sup>99m</sup>Tc-radioligands. We herein present a small library of [<sup>99m</sup>Tc]<b>1</b> mimics generated after structural modifications
in (a) the linker ([<sup>99m</sup>Tc]<b>2</b>, [<sup>99m</sup>Tc]<b>3</b>, [<sup>99m</sup>Tc]<b>4</b>), (b) the peptide
chain ([<sup>99m</sup>Tc]<b>5</b>, [<sup>99m</sup>Tc]<b>6</b>), and (c) the C-terminus ([<sup>99m</sup>Tc]<b>7</b> or [<sup>99m</sup>Tc]<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, [<sup>99m</sup>Tc]<b>1</b>–[<sup>99m</sup>Tc]<b>6</b> exhibited GRPR-specific
tumor uptake, rapidly clearing from normal tissues. [<sup>99m</sup>Tc]<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 [<sup>99m</sup>Tc]<b>1</b> (5.4 ± 0.7%ID/g at 24 h pi)
New Gastrin Releasing Peptide Receptor-Directed [<sup>99m</sup>Tc]Demobesin 1 Mimics: Synthesis and Comparative Evaluation
We have previously reported on the
gastrin releasing peptide receptor (GRPR) antagonist [<sup>99m</sup>Tc]<b>1</b>, ([<sup>99m</sup>Tc]Âdemobesin 1, <sup>99m</sup>Tc-[N<sub>4</sub>′-diglycolate-dPhe<sup>6</sup>,Leu-NHEt<sup>13</sup>]ÂBBNÂ(6–13)). [<sup>99m</sup>Tc]<b>1</b> has
shown superior biological profile compared to analogous agonist-based <sup>99m</sup>Tc-radioligands. We herein present a small library of [<sup>99m</sup>Tc]<b>1</b> mimics generated after structural modifications
in (a) the linker ([<sup>99m</sup>Tc]<b>2</b>, [<sup>99m</sup>Tc]<b>3</b>, [<sup>99m</sup>Tc]<b>4</b>), (b) the peptide
chain ([<sup>99m</sup>Tc]<b>5</b>, [<sup>99m</sup>Tc]<b>6</b>), and (c) the C-terminus ([<sup>99m</sup>Tc]<b>7</b> or [<sup>99m</sup>Tc]<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, [<sup>99m</sup>Tc]<b>1</b>–[<sup>99m</sup>Tc]<b>6</b> exhibited GRPR-specific
tumor uptake, rapidly clearing from normal tissues. [<sup>99m</sup>Tc]<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 [<sup>99m</sup>Tc]<b>1</b> (5.4 ± 0.7%ID/g at 24 h pi)