Novel <sup>177</sup>Lu-Labeled [Thz<sup>14</sup>]Bombesin(6–14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing Peptide Receptor-Expressing Cancer
<b>Background/Objectives:</b> Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one <sup>68</sup>...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/4/449 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | <b>Background/Objectives:</b> Gastrin-releasing peptide receptor is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of reported GRPR-targeted radioligands limits their clinical applications. Our group previously reported one <sup>68</sup>Ga-labeled GRPR antagonist, [<sup>68</sup>Ga]Ga-TacsBOMB5 (<sup>68</sup>Ga-DOTA-Pip-[D-Phe<sup>6</sup>,NMe-Gly<sup>11</sup>,Leu<sup>13</sup>ψThz<sup>14</sup>]Bombesin(6–14)), and two agonists, [<sup>68</sup>Ga]Ga-LW01110 (<sup>68</sup>Ga-DOTA-Pip-[D-Phe<sup>6</sup>,Tle<sup>10</sup>,NMe-His<sup>12</sup>,Thz<sup>14</sup>]Bombesin(6–14)) and [<sup>68</sup>Ga]Ga-LW01142 (<sup>68</sup>Ga-DOTA-Pip-[D-Phe<sup>6</sup>,His<sup>7</sup>,Tle<sup>10</sup>,NMe-His<sup>12</sup>,Thz<sup>14</sup>]Bombesin(6–14)) showing minimal pancreas uptake. Thus, in this study, we prepared their <sup>177</sup>Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [<sup>177</sup>Lu]Lu-AMBA. <b>Methods</b>: GRPR binding affinities were determined by in vitro competition binding assay using PC-3 prostate cancer cells. Longitudinal SPECT/CT imaging and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Dosimetry data were calculated from the biodistribution results. <b>Results</b>: The K<sub>i</sub>(GRPR) values of Lu-TacsBOMB5, Lu-LW01110, Lu-LW01142, and Lu-AMBA were 12.6 ± 1.02, 3.07 ± 0.15, 2.37 ± 0.28, and 0.33 ± 0.16 nM, respectively. SPECT/CT images and biodistribution results demonstrated good tumor accumulation of [<sup>177</sup>Lu]Lu-TacsBOMB5, [<sup>177</sup>Lu]Lu-LW01110, and [<sup>177</sup>Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz<sup>14</sup>]Bombesin(6–14)-derived ligands was significantly lower than that of [<sup>177</sup>Lu]Lu-AMBA at all time points. The calculated absorbed doses of [<sup>177</sup>Lu]Lu-TacsBOMB5, [<sup>177</sup>Lu]Lu-LW01110, and [<sup>177</sup>Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [<sup>177</sup>Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [<sup>177</sup>Lu]Lu-RM2 (429 mGy/MBq). <b>Conclusions</b>: Our data suggest that [<sup>177</sup>Lu]Lu-TacsBOMB5 and [<sup>177</sup>Lu]Lu-LW01142 reduce radiation exposure to the pancreas. However, further optimizations are needed for both radioligands to prolong their tumor retention and enhance treatment efficacy. |
|---|---|
| ISSN: | 1424-8247 |