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>...
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2025-03-01
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| author | Lei Wang Devon E. Chapple Hsiou-Ting Kuo Sara Kurkowska Ryan P. Wilson Wing Sum Lau Pauline Ng Carlos Uribe François Bénard Kuo-Shyan Lin |
| author_facet | Lei Wang Devon E. Chapple Hsiou-Ting Kuo Sara Kurkowska Ryan P. Wilson Wing Sum Lau Pauline Ng Carlos Uribe François Bénard Kuo-Shyan Lin |
| author_sort | Lei Wang |
| collection | DOAJ |
| description | <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. |
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| spelling | doaj-art-503d7b0d4df64f1a90cdae15b92327e02025-08-20T02:18:10ZengMDPI AGPharmaceuticals1424-82472025-03-0118444910.3390/ph18040449Novel <sup>177</sup>Lu-Labeled [Thz<sup>14</sup>]Bombesin(6–14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing Peptide Receptor-Expressing CancerLei Wang0Devon E. Chapple1Hsiou-Ting Kuo2Sara Kurkowska3Ryan P. Wilson4Wing Sum Lau5Pauline Ng6Carlos Uribe7François Bénard8Kuo-Shyan Lin9Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, CanadaDepartment of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada<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.https://www.mdpi.com/1424-8247/18/4/449gastrin-releasing peptide receptorsingle-photon emission computed tomographylutetium-177dosimetryradioligand therapy |
| spellingShingle | Lei Wang Devon E. Chapple Hsiou-Ting Kuo Sara Kurkowska Ryan P. Wilson Wing Sum Lau Pauline Ng Carlos Uribe François Bénard Kuo-Shyan Lin 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 Pharmaceuticals gastrin-releasing peptide receptor single-photon emission computed tomography lutetium-177 dosimetry radioligand therapy |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | gastrin-releasing peptide receptor single-photon emission computed tomography lutetium-177 dosimetry radioligand therapy |
| url | https://www.mdpi.com/1424-8247/18/4/449 |
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