Side-by-side comparison of the two widely studied GRPR radiotracers, radiolabeled NeoB and RM2, in a preclinical setting,European Journal of Nuclear Medicine and Molecular Imaging

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Side-by-side comparison of the two widely studied GRPR radiotracers, radiolabeled NeoB and RM2, in a preclinical setting
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2023-08-16 , DOI: 10.1007/s00259-023-06364-4
T S T Damiana ₁ , P Paraïso ₁ , C de Ridder ₂ , D Stuurman ₁ , Y Seimbille ₁ , S U Dalm ₁

Affiliation

Introduction

NeoB and RM2 are the most investigated gastrin-releasing peptide receptor (GRPR)–targeting radiotracers in preclinical and clinical studies. Therefore, an extensive side-by-side comparison of the two radiotracers is valuable to demonstrate whether one has advantages over the other. Accordingly, this study aims to compare the in vitro and in vivo characteristics of radiolabeled NeoB and RM2 to guide future clinical studies.

Method

The stability of the radiolabeled GRPR analogs was determined in phosphate buffered saline (PBS), and commercially available mouse and human serum. Target affinity was determined by incubating human prostate cancer PC-3 cells with [¹⁷⁷Lu]Lu-NeoB or [¹⁷⁷Lu]Lu-RM2, + / − increasing concentrations of unlabeled NeoB, RM2, or Tyr⁴-bombesin (BBN). To determine uptake and specificity cells were incubated with [¹⁷⁷Lu]Lu-NeoB or [¹⁷⁷Lu]Lu-RM2 + / − Tyr⁴-BBN. Moreover, in vivo studies were performed to determine biodistribution and pharmacokinetics. Finally, radiotracer binding to various GRPR-expressing human cancer tissues was investigated.

Results

Both radiotracers demonstrated high stability in PBS and human serum, but stability in mouse serum decreased substantially over time. Moreover, both radiotracers demonstrated high GRPR affinity and specificity, but a higher uptake of [¹⁷⁷Lu]Lu-NeoB was observed in in vitro studies. In vivo, no difference in tumor uptake was seen. The most prominent difference in uptake in physiological organs was observed in the GRPR-expressing pancreas; [¹⁷⁷Lu]Lu-RM2 had less pancreatic uptake and a shorter pancreatic half-life than [¹⁷⁷Lu]Lu-NeoB. Furthermore, [¹⁷⁷Lu]Lu-RM2 presented with a lower tumor-to-kidney ratio, while the tumor-to-blood ratio was lower for [¹⁷⁷Lu]Lu-NeoB. The autoradiography studies revealed higher binding of radiolabeled NeoB to all human tumor tissues.

Conclusion

Based on these findings, we conclude that the in vivo tumor-targeting capability of radiolabeled NeoB and RM2 is similar. Additional studies are needed to determine whether the differences observed in physiological organ uptakes, i.e., the pancreas, kidneys, and blood, result in relevant differences in organ absorbed doses when the radiotracers are applied for therapeutic purposes.

中文翻译：

在临床前环境中对两种广泛研究的 GRPR 放射性示踪剂（放射性标记的 NeoB 和 RM2）进行并排比较

介绍

NeoB 和 RM2 是临床前和临床研究中研究最多的胃泌素释放肽受体 (GRPR) 靶向放射性示踪剂。因此，对两种放射性示踪剂进行广泛的并排比较对于证明一种放射性示踪剂是否比另一种具有优势很有价值。因此，本研究旨在比较放射性标记的 NeoB 和 RM2 的体外和体内特征，以指导未来的临床研究。

方法

放射性标记的 GRPR 类似物的稳定性在磷酸盐缓冲盐水 (PBS) 以及市售小鼠和人血清中测定。通过将人前列腺癌 PC-3 细胞与 [ ¹⁷⁷ Lu]Lu-NeoB 或 [ ¹⁷⁷ Lu]Lu-RM2 一起孵育来确定靶标亲和力，+/- 增加未标记 NeoB、RM2 或 Tyr ^{4 -}铃蟾肽 (BBN) 的浓度。为了确定摄取和特异性，将细胞与[ ¹⁷⁷ Lu]Lu-NeoB 或[ ¹⁷⁷ Lu]Lu-RM2 + / - Tyr ⁴ -BBN 一起孵育。此外，还进行了体内研究以确定生物分布和药代动力学。最后，研究了放射性示踪剂与各种表达 GRPR 的人类癌症组织的结合。

结果

两种放射性示踪剂在 PBS 和人血清中均表现出高稳定性，但在小鼠血清中的稳定性随着时间的推移而大幅下降。此外，两种放射性示踪剂都表现出高GRPR亲和力和特异性，但在体外研究中观察到[ ¹⁷⁷ Lu]Lu-NeoB的摄取更高。在体内，没有观察到肿瘤摄取的差异。在表达 GRPR 的胰腺中观察到生理器官摄取的最显着差异；与[ ¹⁷⁷ Lu]Lu-NeoB 相比，[ ¹⁷⁷ Lu]Lu-RM2 具有较少的胰腺摄取和较短的胰腺半衰期。此外，[ ¹⁷⁷ Lu]Lu-RM2 呈现出较低的肿瘤与肾脏比率，而[ ¹⁷⁷ Lu]Lu-NeoB 的肿瘤与血液比率较低。放射自显影研究表明，放射性标记的 NeoB 与所有人类肿瘤组织的结合率更高。