Department of Molecular Oncology, BC Cancer, Vancouver, BC V5Z 1L3, Canada.
Department of Radiology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada.
Molecules. 2022 Jun 11;27(12):3777. doi: 10.3390/molecules27123777.
The gastrin-releasing peptide receptor (GRPR) is a G-protein-coupled receptor that is overexpressed in many solid cancers and is a promising target for cancer imaging and therapy. However, high pancreas uptake is a major concern in the application of reported GRPR-targeting radiopharmaceuticals, particularly for targeted radioligand therapy. To lower pancreas uptake, we explored Ga-complexed TacsBOMB2, TacsBOMB3, TacsBOMB4, TacsBOMB5, and TacsBOMB6 derived from a potent GRPR antagonist sequence, [LeuψThz]Bombesin(7-14), and compared their potential for cancer imaging with [Ga]Ga-RM2. The K(GRPR) values of Ga-TacsBOMB2, Ga-TacsBOMB3, Ga-TacsBOMB4, Ga-TacsBOMB5, Ga-TacsBOMB6, and Ga-RM2 were 7.08 ± 0.65, 4.29 ± 0.46, 458 ± 38.6, 6.09 ± 0.95, 5.12 ± 0.57, and 1.51 ± 0.24 nM, respectively. [Ga]Ga-TacsBOMB2, [Ga]Ga-TacsBOMB3, [Ga]Ga-TacsBOMB5, [Ga]Ga-TacsBOMB6, and [Ga]Ga-RM2 clearly show PC-3 tumor xenografts in positron emission tomography (PET) images, while [Ga]Ga-TacsBOMB5 shows the highest tumor uptake (15.7 ± 2.17 %ID/g) among them. Most importantly, the pancreas uptake values of [Ga]Ga-TacsBOMB2 (2.81 ± 0.78 %ID/g), [Ga]Ga-TacsBOMB3 (7.26 ± 1.00 %ID/g), [Ga]Ga-TacsBOMB5 (1.98 ± 0.10 %ID/g), and [Ga]Ga-TacsBOMB6 (6.50 ± 0.36 %ID/g) were much lower than the value of [Ga]Ga-RM2 (41.9 ± 10.1 %ID/g). Among the tested [LeuψThz]Bombesin(7-14) derivatives, [Ga]Ga-TacsBOMB5 has the highest tumor uptake and tumor-to-background contrast ratios, which is promising for clinical translation to detect GRPR-expressing tumors. Due to the low pancreas uptake of its derivatives, [LeuψThz]Bombesin(7-14) represents a promising pharmacophore for the design of GRPR-targeting radiopharmaceuticals, especially for targeted radioligand therapy application.
胃泌素释放肽受体 (GRPR) 是一种 G 蛋白偶联受体，在许多实体瘤中过度表达，是癌症成像和治疗的有前途的靶点。然而，在报告的 GRPR 靶向放射性药物的应用中，胰腺摄取率高是一个主要关注点，特别是对于靶向放射性配体治疗。为了降低胰腺摄取率，我们研究了源自有效 GRPR 拮抗剂序列 [LeuψThz]Bombesin(7-14)的 Ga 配合物 TacsBOMB2、TacsBOMB3、TacsBOMB4、TacsBOMB5 和 TacsBOMB6，并比较了它们与 [Ga]Ga-RM2 用于癌症成像的潜力。Ga-TacsBOMB2、Ga-TacsBOMB3、Ga-TacsBOMB4、Ga-TacsBOMB5、Ga-TacsBOMB6 和 Ga-RM2 的 GRPR 亲和力 (K(GRPR)) 值分别为 7.08 ± 0.65、4.29 ± 0.46、458 ± 38.6、6.09 ± 0.95、5.12 ± 0.57 和 1.51 ± 0.24 nM。[Ga]Ga-TacsBOMB2、[Ga]Ga-TacsBOMB3、[Ga]Ga-TacsBOMB5、[Ga]Ga-TacsBOMB6 和 [Ga]Ga-RM2 清楚地在正电子发射断层扫描 (PET) 图像中显示出 PC-3 肿瘤异种移植，而其中 [Ga]Ga-TacsBOMB5 显示出最高的肿瘤摄取率（15.7 ± 2.17 %ID/g）。最重要的是，[Ga]Ga-TacsBOMB2（2.81 ± 0.78 %ID/g）、[Ga]Ga-TacsBOMB3（7.26 ± 1.00 %ID/g）、[Ga]Ga-TacsBOMB5（1.98 ± 0.10 %ID/g）和 [Ga]Ga-TacsBOMB6（6.50 ± 0.36 %ID/g）的胰腺摄取率远低于 [Ga]Ga-RM2（41.9 ± 10.1 %ID/g）。在测试的 [LeuψThz]Bombesin(7-14) 衍生物中，[Ga]Ga-TacsBOMB5 具有最高的肿瘤摄取率和肿瘤与背景的对比率，这对于临床转化为检测 GRPR 表达肿瘤具有很大的希望。由于其衍生物的胰腺摄取率低，[LeuψThz]Bombesin(7-14) 代表了一种有前途的药效团，可用于设计 GRPR 靶向放射性药物，特别是用于靶向放射性配体治疗应用。
