Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924,European Journal of Nuclear Medicine and Molecular Imaging

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Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924
European Journal of Nuclear Medicine and Molecular Imaging ( IF 8.6 ) Pub Date : 2024-12-11 , DOI: 10.1007/s00259-024-07025-w
Muriel Aline Spahn, Tom Van Loy, Sofie Celen, Michel Koole, Christophe M. Deroose, Christopher Cawthorne, Wim Vanduffel, Dominique Schols, Guy Bormans, Frederik Cleeren

Background

[⁶⁸Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an Al¹⁸F-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18.

Methods

We designed a CXCR4-specific radioprobe, [¹⁸F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable Al¹⁸F-labeling. The in vitro CXCR4 affinity was assessed using cell-based binding assays. Subsequently, in vivo pharmacokinetics and tumor uptake of [¹⁸F]AlF-NOTA-SC were assessed in naïve mice and mice with xenografts derived from U87.CD4/U87.CD4.CXCR4 and MM.1 S cells. Finally, biodistribution was determined in a non-human primate using PET-MR.

Results

Compared to Ga-PentixaFor, AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4. [¹⁸F]AlF-NOTA-SC was produced with a decay-corrected radiochemical yield of 21.0 ± 7.1% and an apparent molar activity of 16.4 ± 3.6 GBq/µmol. In [¹⁸F]AlF-NOTA-SC binding assays on U87.CD4.CXCR4 cells, the total bound fraction was 7.1 ± 0.5% (58% blocking by AMD3100). In naïve mice, the radiotracer did not accumulate in any organs; however, it showed a significant CXCR4-specific uptake in xenografted tumors (SUVmean_U87.CD4 = 0.04 ± 0.00 (n = 3); SUVmean_{U87.CD4.CXCR4} = 3.04 ± 0.65 (n = 3); SUVmean_MM.1 S = 1.95 ± 0.11 (n = 3)). In a non-human primate, [¹⁸F]AlF-NOTA-SC accumulated in CXCR4 expressing organs, such as the spleen and bone marrow.

Conclusion

[¹⁸F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an ¹⁸F-alternative to [⁶⁸Ga]PentixaFor.

Graphical abstract

中文翻译：

使用 Al18F 标记的拮抗剂 LY2510924 对 CXCR4 进行选择性 PET 成像

背景

[⁶⁸加]PentixaFor 可检测 C-X-C 趋化因子受体 4 型（CXCR4）在各种恶性肿瘤（如多发性骨髓瘤和非霍奇金淋巴瘤）以及内分泌和炎症性疾病中的过表达。本研究旨在利用氟 18 的物理和物流优势，开发一种源自 LY2510924 的 Al¹⁸F 标记放射性示踪剂，用于 CXCR4 靶向成像。

方法

我们设计了一种 CXCR4 特异性放射性探针 [¹⁸F]AlF-NOTA-SC，基于LY2510924，通过结合三谷氨酸接头和 NOTA 螯合剂来实现 Al¹⁸F 标记。使用基于细胞的结合测定法评估体外 CXCR4 亲和力。随后，在幼稚小鼠和来源于 U87 的异种移植物小鼠中评估体内药代动力学和 [¹⁸F]AlF-NOTA-SC 的肿瘤摄取。CD4/U87 的。CD4 的。CXCR4 和 MM.1 S 细胞。最后，使用 PET-MR 确定非人灵长类动物中的生物分布。

结果

与 Ga-PentixaFor 相比，AlF-NOTA-SC 对人 CXCR4 表现出相似的体外亲和力。[¹⁸个地址]AlF-NOTA-SC 的衰变校正放射化学产率为 21.0 ± 7.1%，表观摩尔活性为 16.4 ± 3.6 GBq/μmol。在 U87 上的 [¹⁸F]AlF-NOTA-SC 结合测定中。CD4 的。CXCR4 细胞，总结合分数为 7.1 ± 0.5% （AMD3100 封闭 58%）。在幼稚的小鼠中，放射性示踪剂没有在任何器官中积累;然而，它在异种移植肿瘤中显示出显着的 CXCR4 特异性摄取（SUVmean_U87.CD4 = 0.04 ± 0.00 （n = 3）;SUVmean_{U87.CD4.CXCR4} = 3.04 ± 0.65 （n = 3）;SUVmean_MM.1 S = 1.95 ± 0.11 （n = 3））。在非人灵长类动物中，[¹⁸F]AlF-NOTA-SC 积累在表达 CXCR4 的器官中，例如脾脏和骨髓。