Evaluation of [¹⁸F]AlF NOTA-5G, an Aluminum [¹⁸F]fluoride Labeled Peptide Targeting the Cell Surface Receptor Integrin Alpha(v)beta(6) for PET Imaging.

IF 3 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING Molecular Imaging and Biology Pub Date : 2025-02-20 DOI:10.1007/s11307-025-01989-3

Sven H Hausner, Ryan A Davis, Tanushree Ganguly, Rebecca Harris, Julie L Sutcliffe

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Abstract

Purpose: Peptide-based probes targeting integrin α_vβ₆ have shown promise in clinical trials for cancer imaging based on the high over-expression of this epithelial-specific cell surface receptor in many cancerous tissues. Recently, the α_vβ₆-targeting gallium-68 labeled DOTA-5G peptide, [⁶⁸Ga]Ga DOTA-5G, demonstrated diagnostic value in patients with metastatic pancreatic cancer. To facilitate adoption at sites without access to gallium-68 and take advantage of the characteristics of fluorine-18 through convenient [¹⁸F]fluoride chelation chemistry, this study evaluated the fluorine-18 labeled analog, [¹⁸F]AlF NOTA-5G, in vitro and in vivo in a tumor mouse model, and compared it to [⁶⁸Ga]Ga DOTA-5G.

Procedures: NOTA-5G was synthesized on solid phase and radiolabeled with aluminum [¹⁸F]fluoride to generate [¹⁸F]AlF NOTA-5G. Cell binding and internalization of [¹⁸F]AlF NOTA-5G were evaluated in paired DX3puroβ6 (α_vβ₆ +) and DX3puro (α_vβ₆ -), and pancreatic BxPC-3 (α_vβ₆ +) cells. Imaging (1-6 h) and biodistribution were performed in BxPC-3 tumor-bearing mice.

Results: [¹⁸F]AlF NOTA-5G was obtained in > 93% radiochemical purity. Cell binding was α_vβ₆-targeted (1 h: 66% bound to DX3puroβ6, vs 2% to DX3puro), and ≥ 50% of bound activity was internalized; analogous to [⁶⁸Ga]Ga DOTA-5G, PET imaging showed clearly delineated tumors. Excretion remained primarily renal (1 to 4 h: 18.6 to 12.5% ID/g). Tumor uptake remained relatively steady (1 to 4 h: 2.3 ± 0.4 to 1.8 ± 0.6% ID/g - closely matching [⁶⁸Ga]Ga DOTA-5G with 2.6 ± 0.8 and 2.0 ± 0.6% ID/g at 1 and 2 h), resulting in tumor/pancreas, tumor/liver, and tumor/blood ratios of 18/1, 24/1, and 162/1, respectively (4 h); by comparison, for [⁶⁸Ga]Ga DOTA-5G the values were 21/1, 20/1, and 22/1 (2 h).

Conclusions: [¹⁸F]AlF NOTA-5G demonstrated selective α_vβ₆-targeting and tumor uptake similar to [⁶⁸Ga]Ga DOTA-5G. The tumor-to-background ratio resulted high-contrast PET images, with an extended imaging window compared to [⁶⁸Ga]Ga DOTA-5G. The synthesis of [¹⁸F]AlF NOTA-5G is currently being optimized for clinical production.

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目的：基于上皮特异性细胞表面受体αvβ6在许多癌症组织中的高表达，靶向整合素αvβ6的肽类探针在癌症成像的临床试验中显示出前景。最近，αvβ6 靶向镓-68 标记的 DOTA-5G 肽（[68Ga]Ga DOTA-5G）在转移性胰腺癌患者中显示出诊断价值。为了便于在无法获得镓-68的部位采用，并通过方便的[18F]氟化物螯合化学利用氟-18的特性，本研究在肿瘤小鼠模型中对氟-18标记的类似物[18F]AlF NOTA-5G进行了体外和体内评估，并与[68Ga]Ga DOTA-5G进行了比较：在固相上合成 NOTA-5G，并用[18F]氟化铝进行放射性标记，生成[18F]AlF NOTA-5G。在配对的 DX3puroβ6 (αvβ6 +) 和 DX3puro (αvβ6 -) 以及胰腺 BxPC-3 (αvβ6 +) 细胞中评估 [18F]AlF NOTA-5G 的细胞结合和内化情况。在 BxPC-3 肿瘤小鼠体内进行了成像（1-6 h）和生物分布研究：结果：[18F]AlF NOTA-5G 的放射化学纯度大于 93%。细胞结合是以αvβ6为靶点的（1 h：66%与DX3puroβ6结合，2%与DX3puro结合），≥50%的结合活性被内化；与[68Ga]Ga DOTA-5G类似，PET成像显示肿瘤轮廓清晰。排泄仍然主要通过肾脏（1 至 4 小时：18.6% 至 12.5% ID/g）。肿瘤摄取量保持相对稳定（1 至 4 h：2.3 ± 0.4 至 1.8 ± 0.6% ID/g - 与[68Ga]Ga DOTA-5G 在 1 和 4 h 分别为 2.6 ± 0.8 和 2.0 ± 0.6%的ID/g（1小时和2小时），导致肿瘤/胰腺、肿瘤/肝脏和肿瘤/血液的比值分别为18/1、24/1和162/1（4小时）；相比之下，[68Ga]Ga DOTA-5G的比值分别为21/1、20/1和22/1（2小时）：结论：[18F]AlF NOTA-5G表现出与[68Ga]Ga DOTA-5G相似的选择性αvβ6靶向性和肿瘤摄取性。与[68Ga]Ga DOTA-5G相比，[18F]AlF NOTA-5G的肿瘤-背景比可产生高对比度的正电子发射计算机断层图像，并具有更宽的成像窗口。目前正在优化[18F]AlF NOTA-5G的合成，以便用于临床生产。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.