Synthesis and preclinical evaluation of gastrin releasing peptide receptor antagonist [18F]MeTz-PEG2-RM26 for positron emission tomography

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR
Panagiotis Kanellopoulos, Fanny Lundmark, Ayman Abouzayed, Lorenzo Jacopo Ilic Balestri, Esther Olaniran Håkansson, Karim Obeid, Luke R. Odell, Vladimir Tolmachev, Ulrika Rosenström, Jonas Eriksson, Anna Orlova
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Abstract

Background

The gastrin-releasing peptide receptor (GRPR) is overexpressed in the majority of primary prostate cancer lesions, with persistent expression in lymph nodes and bone metastases, making it a legitimate molecular target for diagnostic imaging and staging. This study presents the synthesis and preclinical evaluation of [18F]MeTz-PEG2-RM26, a GRPR antagonist which utilises the Inverse Electron Demand Diels-Alder (IEDDA) reaction for 18F-labelling. This click-chemistry approach allows for site-specific incorporation of fluorine-18 under mild conditions, preserving the peptide’s structural integrity and biological activity. Receptor specificity and affinity of [18F]MeTz-PEG2-RM26 were evaluated in vitro using GRPR-expressing PC-3 cells. Furthermore, the biodistribution profile of [18F]MeTz-PEG2-RM26 was assessed in NMRI mice and its tumour-targeting capability was investigated in mice bearing PC-3 xenografts.

Results

The labelling of TCO-PEG2-RM26 precursor involved three steps: (1) synthesis of an 18F-labelled activated ester on a quaternary methyl ammonium (QMA) cartridge, (2) conjugation of the labelled ester to a tetrazine amine, and (3) attachment to TCO-PEG2-RM26 via an IEDDA click reaction. This production method of [18F]MeTz-PEG2-RM26 afforded a high apparent molar activity of 3.5–4.3 GBq/µmol and radiochemical purity exceeding 98%, with 43–70 MBq activity incorporation, while the entire synthesis was completed within 75 min. Both in vitro and in vivo studies confirmed the specific binding of [18F]MeTz-PEG2-RM26 to GRPR, with a significant reduction in activity uptake observed upon receptor saturation. The radioligand exhibited rapid blood clearance and minimal bone uptake, confirming the stability of the fluorine-carbon bond. However, high hepatic uptake (12–13% IA/g at 1 h post-injection) indicated predominant hepatobiliary excretion. Receptor-mediated uptake was observed in the tumours and pancreatic tissue, although the overall activity uptake in tumours was low, likely due to the rapid hepatobiliary clearance of [18F]MeTz-PEG2-RM26.

Conclusions

These findings demonstrate the effectiveness of the IEDDA click reaction for fluorine-18 labelling of GRPR-targeting PET tracers. Future studies should focus on increasing the hydrophilicity of the imaging probe to improve the targeting properties and biodistribution profile of the radioligand.

胃泌素释放肽受体拮抗剂MeTz-PEG2-RM26的合成及临床前评价[18F]
胃泌素释放肽受体(GRPR)在大多数原发性前列腺癌病变中过表达,在淋巴结和骨转移灶中持续表达,使其成为诊断成像和分期的合法分子靶点。本研究介绍了[18F]MeTz-PEG2-RM26的合成和临床前评价,这是一种利用逆电子需求Diels-Alder (IEDDA)反应进行18F标记的GRPR拮抗剂。这种点击化学方法允许在温和条件下将氟-18特定位点结合,保持肽的结构完整性和生物活性。使用表达grpr的PC-3细胞体外评估[18F]MeTz-PEG2-RM26的受体特异性和亲和力。此外,我们在NMRI小鼠中评估了[18F]MeTz-PEG2-RM26的生物分布,并在移植PC-3的小鼠中研究了其肿瘤靶向能力。结果TCO-PEG2-RM26前体的标记包括三个步骤:(1)在季甲基铵(QMA)药筒上合成18f标记的活化酯,(2)标记的酯与四嗪胺结合,(3)通过IEDDA点击反应与TCO-PEG2-RM26结合。[18F]MeTz-PEG2-RM26的这种生产方法具有3.5-4.3 GBq/µmol的高表观摩尔活性,放射化学纯度超过98%,43-70 MBq的活性结合,而整个合成在75分钟内完成。体外和体内研究证实了[18F]MeTz-PEG2-RM26与GRPR的特异性结合,在受体饱和时观察到活性摄取显著减少。放射性配体表现出快速的血液清除和最小的骨摄取,证实了氟-碳键的稳定性。然而,高肝脏摄取(注射后1小时12-13% IA/g)表明主要是肝胆排泄。在肿瘤和胰腺组织中观察到受体介导的摄取,尽管肿瘤的总体活性摄取较低,可能是由于[18F]MeTz-PEG2-RM26的肝胆快速清除。结论IEDDA点击反应可用于grpr靶向PET示踪剂的氟-18标记。未来的研究应侧重于提高成像探针的亲水性,以改善放射性配体的靶向性和生物分布特征。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.20
自引率
8.70%
发文量
30
审稿时长
5 weeks
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