Synthesis and preclinical evaluation of [18F]AlF-NOTA-Asp2-PEG2-JR11 as a novel antagonist radioligand for PET imaging of somatostatin receptor

IF 8.6 1区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING European Journal of Nuclear Medicine and Molecular Imaging Pub Date : 2024-11-13 DOI:10.1007/s00259-024-06978-2

Haoran Liang, Zihao Chen, Chunwei Mo, Yanjiang Han, Qingxing Liu, Ganghua Tang

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Abstract

Purpose

Somatostatin receptor (SSTR) antagonists have recently emerged as preferable radiotracers for SSTR-targeted imaging and therapy. This study aimed to design a novel SSTR antagonist, [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11, and compare its preclinical performance with the previously reported antagonist, [¹⁸F]AlF-NOTA-JR11, and the agonist [⁶⁸Ga]Ga-DOTA-TATE.

Methods

[¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 was synthesized via a one-step radiolabeling process involving [¹⁸F]AlF chelation. The binding affinity, internalization, and cellular uptake were evaluated using AR42J/SSTR + cells. Biodistribution and PET/CT imaging were conducted in mice bearing xenografted AR42J/SSTR + or HCT116/SSTR- tumor xenografts.

Results

[¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 was manually synthesized within 30 min with an uncorrected radiochemical yield of 39.56 ± 3.25% (n > 5) and radiochemical purity (RCP) exceeding 99% (n > 5). [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 demonstrated excellent in vivo stability over 2 h (RCP > 95%). Among AR42J cells, [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 exhibited high affinity, specific uptake, and low internalization, similar to [¹⁸F]AlF-NOTA-JR11. Biodistribution and micro-PET/CT imaging studies revealed comparable tumor uptake between [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 and [¹⁸F]AlF-NOTA-JR11 (9.26 ± 0.49 vs. 10.18 ± 0.82%ID/g, p = 0.147) at 60 min post-injection (p.i), both were significantly higher than [⁶⁸Ga]Ga-DOTA-TATE (6.79 ± 0.29%ID/g, p = 0.001). Co-injecting the corresponding inhibitor significantly reduced the tumor uptake of all three tracers. Notably, [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 reached peak tumor uptake at 30 min p.i. and exhibited the lowest uptake and fastest clearance in most normal organs, including the kidney, bone, liver, and muscle, resulting in the highest and increasing tumor-to-background ratios (TBR) over time among the three tracers.

Conclusion

The synthesis of [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 is efficient, with high radiochemical yield and RCP. [¹⁸F]AlF-NOTA-Asp₂-PEG₂-JR11 exhibits excellent in vivo stability, high tumor uptake, and superior TBR, making it a promising potential tracer for imaging SSTR-positive tumors.

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合成[18F]AlF-NOTA-Asp2-PEG2-JR11 并对其进行临床前评估，将其作为用于体生长激素受体 PET 成像的新型拮抗剂放射性配体

目的索马司他汀受体（SSTR）拮抗剂最近已成为 SSTR 靶向成像和治疗的首选放射性同位素。本研究旨在设计一种新型 SSTR 拮抗剂 [18F]AlF-NOTA-Asp2-PEG2-JR11，并将其临床前表现与之前报道的拮抗剂 [18F]AlF-NOTA-JR11 和激动剂 [68Ga]Ga-DOTA-TATE 进行比较。使用 AR42J/SSTR + 细胞对其结合亲和力、内化和细胞摄取进行了评估。结果[18F]AlF-NOTA-Asp2-PEG2-JR11在30分钟内人工合成，未校正放射化学收率为39.56±3.25%（n >5），放射化学纯度（RCP）超过99%（n >5）。[18F]AlF-NOTA-Asp2-PEG2-JR11在2小时内表现出极佳的体内稳定性（RCP >95%）。在 AR42J 细胞中，[18F]AlF-NOTA-Asp2-PEG2-JR11 表现出与[18F]AlF-NOTA-JR11 相似的高亲和性、特异性摄取和低内化。生物分布和显微PET/CT成像研究显示，在注射后60分钟（p.i），[18F]AlF-NOTA-Asp2-PEG2-JR11和[18F]AlF-NOTA-JR11的肿瘤摄取率相当（9.26 ± 0.49 vs. 10.18 ± 0.82%ID/g，p = 0.147），均显著高于[68Ga]Ga-DOTA-TATE（6.79 ± 0.29%ID/g，p = 0.001）。同时注射相应的抑制剂可明显降低三种示踪剂对肿瘤的摄取。值得注意的是，[18F]AlF-NOTA-Asp2-PEG2-JR11在30 min p.i.达到肿瘤摄取峰值，而在肾脏、骨骼、肝脏和肌肉等大多数正常器官中的摄取最低、清除最快，因此在三种示踪剂中肿瘤与背景比（TBR）最高，且随时间推移不断升高。[18F]AlF-NOTA-Asp2-PEG2-JR11在体内表现出卓越的稳定性、高肿瘤摄取率和优异的TBR，使其有望成为SSTR阳性肿瘤成像的潜在示踪剂。

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来源期刊

European Journal of Nuclear Medicine and Molecular Imaging 医学-核医学

CiteScore

15.60

自引率

9.90%

发文量

392

审稿时长

3 months

期刊介绍： The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.