胃泌素释放肽受体(GRPR)是一种G蛋白偶联受体,在许多实体癌中过度表达,是癌症成像和治疗的有希望的靶标。然而,高胰腺摄取是应用报道的GRPR靶向放射性药物的主要问题,特别是靶向放射性配体治疗。为了降低胰腺的摄取,我们探索了来自有效的GRPR拮抗剂序列的Ga复合的TacsBOMB2,TacsBOMB3,TacsBOMB4,TacsBOMB5和TacsBOMB6,[Leu13üThz14]Bombesin(7-14),并比较了它们与[68Ga]Ga-RM2的癌症成像潜力。Ga-TacsBOMB2、Ga-TacsBOMB3、Ga-TacsBOMB4、Ga-TacsBOMB5、Ga-TacsBOMB6和Ga-RM2的Ki(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±0.24nM分别。[68Ga]Ga-TacsBOMB2,[68Ga]Ga-TacsBOMB3,[68Ga]Ga-TacsBOMB5,[68Ga]Ga-TacsBOMB6和[68Ga]Ga-RM2在正电子发射断层扫描(PET)图像中清楚显示PC-3肿瘤异种移植物,其中[68Ga]Ga-TacsBOMB5显示最高的肿瘤摄取(15.7±2.17%ID/g)。最重要的是,[68Ga]Ga-TacsBOMB2的胰腺摄取值(2.81±0.78%ID/g),[68Ga]Ga-TacsBOMB3(7.26±1.00%ID/g),[68Ga]Ga-TacsBOMB5(1.98±0.10%ID/g),[68Ga]Ga-TacsBOMB6(6.50±0.36%ID/g)远低于[68Ga]Ga-RM2(41.9±10.1%ID/g)的值。在已测试的[Leu13Thz14]Bombesin(7-14)衍生物中,[68Ga]Ga-TacsBOMB5具有最高的肿瘤摄取和肿瘤背景对比度,这是有希望的临床翻译检测GRPR表达的肿瘤。由于其衍生物的低胰腺摄取,[Leu13bertThz14]Bombesin(7-14)代表了用于GRPR靶向放射性药物设计的有前途的药效团,特别是靶向放射性配体治疗的应用。
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, [Leu13ψThz14]Bombesin(7-14), and compared their potential for cancer imaging with [68Ga]Ga-RM2. The Ki(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. [68Ga]Ga-TacsBOMB2, [68Ga]Ga-TacsBOMB3, [68Ga]Ga-TacsBOMB5, [68Ga]Ga-TacsBOMB6, and [68Ga]Ga-RM2 clearly show PC-3 tumor xenografts in positron emission tomography (PET) images, while [68Ga]Ga-TacsBOMB5 shows the highest tumor uptake (15.7 ± 2.17 %ID/g) among them. Most importantly, the pancreas uptake values of [68Ga]Ga-TacsBOMB2 (2.81 ± 0.78 %ID/g), [68Ga]Ga-TacsBOMB3 (7.26 ± 1.00 %ID/g), [68Ga]Ga-TacsBOMB5 (1.98 ± 0.10 %ID/g), and [68Ga]Ga-TacsBOMB6 (6.50 ± 0.36 %ID/g) were much lower than the value of [68Ga]Ga-RM2 (41.9 ± 10.1 %ID/g). Among the tested [Leu13ψThz14]Bombesin(7-14) derivatives, [68Ga]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, [Leu13ψThz14]Bombesin(7-14) represents a promising pharmacophore for the design of GRPR-targeting radiopharmaceuticals, especially for targeted radioligand therapy application.