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新型低胰腺聚集的镥标记[Thz]蛙皮素（6-14）衍生物用于靶向表达胃泌素释放肽受体的癌症

Novel Lu-Labeled [Thz]Bombesin(6-14) Derivatives with Low Pancreas Accumulation for Targeting Gastrin-Releasing Peptide Receptor-Expressing Cancer.

作者信息

Wang Lei, Chapple Devon E, Kuo Hsiou-Ting, Kurkowska Sara, Wilson Ryan P, Lau Wing Sum, Ng Pauline, Uribe Carlos, Bénard François, Lin Kuo-Shyan

机构信息

Department of Molecular Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.

Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC V5Z 1L3, Canada.

出版信息

Pharmaceuticals (Basel). 2025 Mar 23;18(4):449. doi: 10.3390/ph18040449.

DOI:10.3390/ph18040449
PMID:40283887
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12030706/
Abstract

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 Ga-labeled GRPR antagonist, [Ga]Ga-TacsBOMB5 (Ga-DOTA-Pip-[D-Phe,NMe-Gly,LeuψThz]Bombesin(6-14)), and two agonists, [Ga]Ga-LW01110 (Ga-DOTA-Pip-[D-Phe,Tle,NMe-His,Thz]Bombesin(6-14)) and [Ga]Ga-LW01142 (Ga-DOTA-Pip-[D-Phe,His,Tle,NMe-His,Thz]Bombesin(6-14)) showing minimal pancreas uptake. Thus, in this study, we prepared their Lu-labeled analogs, evaluated their therapeutic potentials, and compared them with the clinically evaluated [Lu]Lu-AMBA. : 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. : The K(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 [Lu]Lu-TacsBOMB5, [Lu]Lu-LW01110, and [Lu]Lu-LW01142 at early time points with rapid clearance over time. The pancreas uptake of all three [Thz]Bombesin(6-14)-derived ligands was significantly lower than that of [Lu]Lu-AMBA at all time points. The calculated absorbed doses of [Lu]Lu-TacsBOMB5, [Lu]Lu-LW01110, and [Lu]Lu-LW01142 in PC-3 tumor xenografts were 87.1, 312, and 312 mGy/MBq, respectively, higher than that of [Lu]Lu-AMBA (79.1 mGy/MBq), but lower than that of the previously reported [Lu]Lu-RM2 (429 mGy/MBq). : Our data suggest that [Lu]Lu-TacsBOMB5 and [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.

摘要

胃泌素释放肽受体是癌症诊断和治疗的一个有前景的靶点。然而，已报道的靶向GRPR的放射性配体在胰腺中的高摄取限制了它们的临床应用。我们团队之前报道了一种镓标记的GRPR拮抗剂，[Ga]Ga-TacsBOMB5（Ga-DOTA-Pip-[D-苯丙氨酸，N-甲基甘氨酸，亮氨酸ψ噻唑]蛙皮素(6 - 14)），以及两种激动剂，[Ga]Ga-LW01110（Ga-DOTA-Pip-[D-苯丙氨酸，叔亮氨酸，N-甲基组氨酸，噻唑]蛙皮素(6 - 14)）和[Ga]Ga-LW01142（Ga-DOTA-Pip-[D-苯丙氨酸，组氨酸，叔亮氨酸，N-甲基组氨酸，噻唑]蛙皮素(6 - 14)），它们在胰腺中的摄取极少。因此，在本研究中，我们制备了它们的镥标记类似物，评估了它们的治疗潜力，并将它们与临床评估的[Lu]Lu-AMBA进行比较。：使用PC-3前列腺癌细胞通过体外竞争结合试验测定GRPR结合亲和力。在荷PC-3肿瘤的小鼠中进行纵向SPECT/CT成像和离体生物分布研究。根据生物分布结果计算剂量学数据。：Lu-TacsBOMB5、Lu-LW01110、Lu-LW01142和Lu-AMBA的K(GRPR)值分别为12.6±1.02、3.07±0.15、2.37±0.28和0.33±0.16 nM。SPECT/CT图像和生物分布结果表明，[Lu]Lu-TacsBOMB5、[Lu]Lu-LW01110和[Lu]Lu-LW01142在早期时间点有良好的肿瘤蓄积，且随时间快速清除。在所有时间点，所有三种[噻唑]蛙皮素(6 - 14)衍生配体的胰腺摄取均显著低于[Lu]Lu-AMBA。在PC-3肿瘤异种移植物中，[Lu]Lu-TacsBOMB5、[Lu]Lu-LW01110和[Lu]Lu-LW01142的计算吸收剂量分别为87.1、312和312 mGy/MBq，高于[Lu]Lu-AMBA（79.1 mGy/MBq），但低于先前报道的[Lu]Lu-RM2（429 mGy/MBq）。：我们的数据表明，[Lu]Lu-TacsBOMB5和[Lu]Lu-LW01142减少了对胰腺的辐射暴露。然而，这两种放射性配体都需要进一步优化，以延长它们在肿瘤中的滞留时间并提高治疗效果。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/7fed85ca12f5/pharmaceuticals-18-00449-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/dda9f8dca44d/pharmaceuticals-18-00449-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/7fed85ca12f5/pharmaceuticals-18-00449-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/53b8ccede5f8/pharmaceuticals-18-00449-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/c31bc106f614/pharmaceuticals-18-00449-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/8e0f578f2b63/pharmaceuticals-18-00449-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/746ceaba7b4e/pharmaceuticals-18-00449-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/fc1bc9634de6/pharmaceuticals-18-00449-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/58006491bc85/pharmaceuticals-18-00449-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/dda9f8dca44d/pharmaceuticals-18-00449-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1a86/12030706/7fed85ca12f5/pharmaceuticals-18-00449-g009.jpg

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