Bratanovic Ivica J, Zhang Chengcheng, Zhang Zhengxing, Kuo Hsiou-Ting, Colpo Nadine, Zeisler Jutta, Merkens Helen, Uribe Carlos, Lin Kuo-Shyan, Bénard François
BC Cancer, Vancouver, British Columbia, Canada.
Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; and.
J Nucl Med. 2022 Mar;63(3):424-430. doi: 10.2967/jnumed.120.257758. Epub 2021 Jul 22.
The gastrin-releasing peptide receptor (GRPR) is overexpressed in many solid malignancies, particularly in prostate and breast cancers, among others. We synthesized ProBOMB2, a novel bombesin derivative radiolabeled with Ga and Lu, and evaluated its ability to target GRPR in a preclinical model of human prostate cancer. ProBOMB2 was synthesized in solid phase using fluorenylmethoxycarbonyl chemistry. The chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid was coupled to the terminus and separated from the GRPR-targeting sequence by a cationic 4-amino-(1-carboxymethyl)-piperidine spacer. Binding affinity for both human and murine GRPR was determined using a cell-based competition assay, whereas a calcium efflux assay was used to measure the agonist and antagonist properties of the derivatives. ProBOMB2 was radiolabeled with Lu and Ga. SPECT and PET imaging and biodistribution studies were conducted using male immunocompromised mice bearing GRPR-positive PC-3 human prostate cancer xenografts. Ga-ProBOMB2 and Lu-ProBOMB2 bound to PC-3 cells with an inhibition constant of 4.58 ± 0.67 and 7.29 ± 1.73 nM, respectively. Ga-ProBOMB2 and Lu-ProBOMB2 were radiolabeled with a radiochemical purity greater than 95%. Both radiotracers were excreted primarily via the renal pathway. PET images of PC-3 tumor xenografts were visualized with excellent contrast at 1 and 2 h after injection with Ga-ProBOMB2, and there was very low off-target organ accumulation. Lu-ProBOMB2 enabled clear visualization of PC-3 tumor xenografts by SPECT imaging at 1, 4, and 24 h after injection Lu-ProBOMB2 displayed higher tumor uptake than Ga-ProBOMB2 at 1 h after injection. Lu-ProBOMB2 tumor uptake at 1, 4, and 24 h after injection was 14.9 ± 3.1, 4.8 ± 2.1, and 1.7 ± 0.3 percentage injected dose per gram of tissue, respectively. Ga-ProBOMB2 and Lu-ProBOMB2 are promising radiotracers with limited pancreas uptake, good tumor uptake, and favorable pharmacokinetics for imaging and therapy of GRPR-expressing tumors.
胃泌素释放肽受体（GRPR）在许多实体恶性肿瘤中过度表达，尤其是在前列腺癌和乳腺癌等肿瘤中。我们合成了ProBOMB2，一种用镓和镥进行放射性标记的新型蛙皮素衍生物，并在人前列腺癌的临床前模型中评估了其靶向GRPR的能力。ProBOMB2采用芴甲氧羰基化学方法在固相合成。螯合剂1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸与N端偶联，并通过阳离子4-氨基-（1-羧甲基）-哌啶间隔基与GRPR靶向序列分离。使用基于细胞的竞争试验测定对人和小鼠GRPR的结合亲和力，而使用钙外流试验测量衍生物的激动剂和拮抗剂特性。ProBOMB2用镥和镓进行放射性标记。使用携带GRPR阳性PC-3人前列腺癌异种移植瘤的雄性免疫受损小鼠进行单光子发射计算机断层扫描（SPECT）和正电子发射断层扫描（PET）成像以及生物分布研究。Ga-ProBOMB2和Lu-ProBOMB2与PC-3细胞结合的抑制常数分别为4.58±0.67和7.29±1.73 nM。Ga-ProBOMB2和Lu-ProBOMB2的放射性化学纯度大于95%进行放射性标记。两种放射性示踪剂主要通过肾脏途径排泄。注射Ga-ProBOMB2后1小时和2小时，PC-3肿瘤异种移植瘤的PET图像对比度良好，且非靶器官累积非常低。注射Lu-ProBOMB2后1小时、4小时和24小时，通过SPECT成像能够清晰显示PC-3肿瘤异种移植瘤。注射后1小时，Lu-ProBOMB2的肿瘤摄取高于Ga-ProBOMB2。注射后1小时、4小时和24小时，Lu-ProBOMB2的肿瘤摄取分别为每克组织14.9±3.1、4.8±2.1和1.7±0.3注射剂量百分比。Ga-ProBOMB2和Lu-ProBOMB2是很有前景的放射性示踪剂，胰腺摄取有限，肿瘤摄取良好，并且对于表达GRPR的肿瘤的成像和治疗具有良好的药代动力学。
