Abstract

Malignant melanoma is an aggressive cancer with poor prognosis. Very late antigen-4 (VLA-4) is overexpressed in melanoma and many other tumors, making it an attractive target for developing molecular diagnostic and therapeutic agents. We compared Al¹⁸F- and ⁶⁸Ga-labeled LLP2A peptides for PET imaging of VLA-4 expression in melanoma. The peptidomimetic ligand LLP2A was modified with chelator 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid (p-SCN-Bn-NOTA), and the resulting NOTA-PEG₄-LLP2A peptide was then radiolabeled with Al¹⁸F or ⁶⁸Ga. The two labeled peptides were assayed for in vitro and in vivo VLA-4 targeting efficiency. Good Al¹⁸F and ⁶⁸Ga radiolabeling yields were achieved, and the resulting PET tracers showed good serum stability. In the in vivo evaluation of the B16F10 xenograft mouse model, both tracers exhibited high accumulation with good contrast in static PET images. Compared with ⁶⁸Ga-NOTA-PEG₄-LLP2A, Al¹⁸F-NOTA-PEG₄-LLP2A resulted in relatively higher background, including higher liver uptake (1 h: 20.1 ± 2.6 vs. 15.3 ± 1.7%ID/g, P < 0.05; 2 h: 11.0 ± 1.2 vs. 8.0 ± 0.8%ID/g, P < 0.05) and lower tumor-to-blood ratios (2.5 ± 0.4 vs. 3.3 ± 0.5 at 1 h, P < 0.05; 5.1 ± 0.9 vs. 7.3 ± 0.6 at 2 h, P < 0.01) at some time points. The results obtained from the mice blocked with unlabeled peptides and VLA-4-negative A375 xenografts groups confirmed the high specificity of the developed tracers. Despite the relatively high liver uptake, both Al¹⁸F-NOTA-PEG₄-LLP2A and ⁶⁸Ga-NOTA-PEG₄-LLP2A exhibited high VLA-4 targeting efficacy with comparable in vivo performance, rendering them promising candidates for imaging tumors that overexpress VLA-4.

Graphic abstract

中文翻译：

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Al 18 F和68 Ga标记的NOTA-PEG 4 -LLP2A在黑色素瘤中非常晚期抗原4的PET成像中的比较

摘要

恶性黑色素瘤是一种侵袭性癌症，预后较差。晚期抗原4（VLA-4）在黑色素瘤和许多其他肿瘤中过表达，使其成为开发分子诊断和治疗剂的有吸引力的靶标。我们比较了Al ¹⁸ F和⁶⁸ Ga标记的LLP2A肽对黑色素瘤中VLA-4表达的PET成像。用螯合剂2 - S-（4-异硫氰酸根合苄基）-1,4,7-三氮杂环壬烷-1,4,7-三乙酸（p -SCN-Bn-NOTA）修饰拟肽配体LLP2A ，并生成NOTA-PEG然后用Al ¹⁸ F或⁶⁸放射性标记₄ -LLP2A肽Ga。测定了两种标记的肽的体外和体内VLA-4靶向效率。获得了良好的Al ¹⁸ F和⁶⁸ Ga放射标记产率，并且所得的PET示踪剂显示出良好的血清稳定性。在B16F10异种移植小鼠模型的体内评估中，两种示踪剂在静态PET图像中均显示出高聚集度和良好的对比度。与⁶⁸ Ga-NOTA-PEG ₄ -LLP2A相比，Al ¹⁸ F-NOTA-PEG ₄ -LLP2A导致相对较高的背景，包括更高的肝脏摄取（1小时：20.1±2.6与15.3±1.7％ID / g，P  <0.05; 2小时：11.0±1.2与8.0±0.8％ID / g，P <0.05）和较低的肿瘤血比（1小时时2.5±0.4 vs. 3.3±0.5，P  <0.05; 2小时时5.1±0.9 vs. 7.3±0.6，P  <0.01）。从未标记肽和VLA-4阴性A375异种移植物阻断的小鼠获得的结果证实了开发的示踪剂具有高度特异性。尽管肝脏摄取相对较高，但Al ¹⁸ F-NOTA-PEG ₄ -LLP2A和⁶⁸ Ga-NOTA-PEG ₄ -LLP2A均显示出高VLA-4靶向功效，且具有可比的体内性能，这使其成为有望对过表达的肿瘤进行成像的候选药物VLA-4。

图形摘要