Synthesis and Evaluation of <sup>68</sup>Ga- and <sup>177</sup>Lu-Labeled [diF-Pro<sup>14</sup>]Bombesin(6−14) Analogs for Detection and Radioligand Therapy of Gastrin-Releasing Peptide Receptor-Expressing Cancer
<b>Background/Objectives:</b> Overexpressed in various solid tumors, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of the current clinically evaluated GRPR-targeted radiopharmaceuticals limits their...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/2/234 |
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| Summary: | <b>Background/Objectives:</b> Overexpressed in various solid tumors, the gastrin-releasing peptide receptor (GRPR) is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake of the current clinically evaluated GRPR-targeted radiopharmaceuticals limits their applications. In this study, we replaced the Pro<sup>14</sup> residue in our previously reported GRPR-targeted LW02056 and ProBOMB5 with 4,4-difluoroproline (diF-Pro) to obtain an agonist LW02060 (DOTA-Pip-[D-Phe<sup>6</sup>,Tle<sup>10</sup>,NMe-His<sup>12</sup>,diF-Pro<sup>14</sup>]Bombesin(6–14)) and an antagonist LW02080 (DOTA-Pip-[D-Phe<sup>6</sup>,NMe-Gly<sup>11</sup>,Leu<sup>13</sup>(ψ)diF-Pro<sup>14</sup>]Bombesin(6–14)), respectively. <b>Methods/Results</b>: The binding affinities (K<sub>i</sub>) of Ga-LW02060, Ga-LW02080, Lu-LW02060, and Lu-LW02080 were measured by in vitro competition binding assays using PC-3 cells and were found to be 5.57 ± 2.47, 21.7 ± 6.69, 8.00 ± 2.61, and 32.1 ± 8.14 nM, respectively. The <sup>68</sup>Ga- and <sup>177</sup>Lu-labeled ligands were obtained in 36–75% decay-corrected radiochemical yields with >95% radiochemical purity. PET imaging, SPECT imaging, and ex vivo biodistribution studies were conducted in PC-3 tumor-bearing mice. Both [<sup>68</sup>Ga]Ga-LW02060 and [<sup>68</sup>Ga]Ga-LW02080 enabled clear tumor visualization in PET images at 1 h post-injection (pi). Tumor uptake values of [<sup>68</sup>Ga]Ga-LW02060 and [<sup>68</sup>Ga]Ga-LW02080 at 1 h pi were 16.8 ± 2.70 and 7.36 ± 1.33 %ID/g, respectively, while their pancreas uptake values were 3.12 ± 0.89 and 0.38 ± 0.04 %ID/g, respectively. Compared to [<sup>177</sup>Lu]Lu-LW02080, [<sup>177</sup>Lu]Lu-LW02060 showed higher tumor uptake at all time points (1, 4, 24, 72, and 120 h pi). However, fast tumor clearance was observed for both [<sup>177</sup>Lu]Lu-LW02060 and [<sup>177</sup>Lu]Lu-LW02080. <b>Conclusions:</b> Our data demonstrate that [<sup>68</sup>Ga]Ga-LW02060 is promising for clinical translation for the detection of GRPR-expressing tumor lesions. However, further optimizations are needed for [<sup>177</sup>Lu]Lu-LW02060 and [<sup>177</sup>Lu]Lu-LW02080 to prolong tumor retention for therapeutic applications. |
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| ISSN: | 1424-8247 |