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.

中文翻译：

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[18F]AlF-NOTA-Asp2-PEG2-JR11 作为生长抑素受体 PET 成像的新型拮抗剂放射性配体的合成和临床前评价

 目的

生长抑素受体 （SSTR） 拮抗剂最近已成为 SSTR 靶向成像和治疗的首选放射性示踪剂。本研究旨在设计一种新型 SSTR 拮抗剂 [¹⁸F]AlF-NOTA-Asp_2-PEG 2-JR11，并将其临床前性能与先前报道的拮抗剂 [¹⁸F]AlF-NOTA-JR11 和激动剂 [⁶⁸Ga]Ga-DOTA-TATE 进行比较。

 方法

[¹⁸个地址]AlF-NOTA-Asp_2-PEG 2-JR11 是通过涉及 [¹⁸F]AlF 螯合的一步放射性标记工艺合成的。使用 AR42J/SSTR + 细胞评估结合亲和力、内化和细胞摄取。在携带异种移植物的 AR42J/SSTR + 或 HCT116/SSTR- 肿瘤异种移植物的小鼠中进行生物分布和 PET/CT 成像。

 结果

[¹⁸个地址]在 30 分钟内手动合成 AlF-NOTA-Asp_2-PEG 2-JR11，未校正放射化学产率为 39.56 ± 3.25% （n > 5），放射化学纯度 （RCP） 超过 99% （n > 5）。[¹⁸个地址]AlF-NOTA-Asp_{2-PEG 2-JR11} 在 2 小时内表现出优异的体内稳定性 （RCP > 95%）。在 AR42J 细胞中，[¹⁸F]AlF-NOTA-Asp_2-PEG 2-JR11 表现出高亲和力、特异性摄取和低内化，类似于 [¹⁸F]AlF-NOTA-JR11。生物分布和显微 PET/CT 成像研究显示，[¹⁸F]AlF-NOTA-Asp_2-PEG 2-JR11 和 [¹⁸F]AlF-NOTA-JR11 之间的肿瘤摄取相当 （9.26 ± 0.49 vs. 10.18 ± 0.82%ID/g，p = 0.147） 在注射后 60 分钟 （p.i） 均显著高于 [⁶⁸Ga]Ga-DOTA-TATE （6.79 ± 0.29%ID/g，p = 0.001）。共同注射相应的抑制剂显着降低了所有三种示踪剂的肿瘤摄取。值得注意的是，[¹⁸F]AlF-NOTA-Asp 2-PEG 2-JR11 在 30 min pi 时达到肿瘤摄取峰值，并且在大多数正常器官（包括肾脏、骨骼、肝脏和肌肉）中表现出最低的摄取和最快的清除率，导致三种示踪剂中的肿瘤背景比 （TBR） 最高且随着时间的推移而增加。

 结论

[¹⁸F]AlF-NOTA-Asp_2-PEG 2-JR11 的合成效率高，放射化学产率和 RCP 高。[¹⁸个地址]AlF-NOTA-Asp_{2-PEG 2-JR11} 表现出优异的体内稳定性、高肿瘤摄取和优异的 TBR，使其成为 SSTR 阳性肿瘤成像的有前途的潜在示踪剂。