High-Contrast CXCR4-Targeted 18F-PET Imaging Using a Potent and Selective Antagonist
High-Contrast CXCR4-Targeted 18F-PET Imaging Using a Potent and Selective Antagonist
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DOI：
10.1021/acs.molpharmaceut.0c00785
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发表时间：
2021-01-04
影响因子：
4.9
通讯作者：
Benard, Francois
中科院分区：
文献类型：
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作者：
Kwon, Daniel;Lozada, Jerome;Benard, Francois
C-X-C趋化因子受体4 （CXCR4）在癌症中高表达，促进肿瘤的增殖、转移和不良预后。CXCR4的无创成像可以检测和表征预后不良的侵袭性癌症。目前，没有f -18标记的CXCR4正电子发射断层扫描（PET）放射性示踪剂显示出可与[Ga-68]Ga-Pentixafor（一种靶向CXCR4的放射性配体）相比的成像对比度。因此，我们旨在通过将亲水性连接剂和三氟硼酸盐放射性假体结合到LY2510924（一种已知的CXCR4拮抗剂）中，开发一种高对比度靶向CXCR4的放射性示踪剂。羧基-氨甲基-三氟硼酸酯（PepBF(3)）通过酰胺键与ly2510924衍生的具有甘油三酯连接剂的肽结合得到BL08，而炔基氨甲基-三氟硼酸酯（AMBF(3)）通过铜催化的[3+2]环加成键反应得到BL09。利用F-18- f -19同位素交换，用[F-18]氟离子对BL08和BL09进行放射性标记。用[Ga-68]GaCl3对pentxafor进行放射性标记。对携带Daudi Burkitt淋巴瘤异种移植的免疫功能低下小鼠进行了并排PET成像和生物分布研究。[F-18]BL08和[18F]BL09的生物分布在注射后2小时显示肿瘤摄取（p.i）。（分别为5.67 +/- 1.25%ID/g和5.83 +/- 0.92%ID/g），与PET成像结果一致。[F-18]BL08具有低背景活性，肿瘤与血液、肌肉和肝脏的比值分别为72 +/- 20、339 +/- 81和14 +/- 3 （2 h p.i）。[F-18]BL09表现相似，比值分别为64 +/- 20、239 +/- 72和17 +/- 3 （2 h p.i）。这导致两种放射性示踪剂在PET成像上的肿瘤高对比度可视化。[F-18]BL08表现出较低的肾摄取（2.2 +/- 0.5%ID/g），与[F-18]BL09相比（7.6 +/- 1.0%ID/g）。与[Ga-68]Ga-Pentixafor相比，[F-18]BL08和[F-18]BL09表现出较高的肿瘤-血液，-肌肉和-肝脏比率（分别为18.9 +/- 2.7,95.4 +/- 36.7和5.9 +/- 0.7）。综上所述，[F-18]BL08和[F-18]BL09能够高对比度地显示Daudi异种移植物中CXCR4的表达。基于高肿瘤与器官比例，[F-18]BL08可能被证明是一种有价值的新工具，用于cxcr4靶向PET成像，具有翻译潜力。使用PepBF3片段是三氟硼酸盐正交偶联的一种新方法，用于肽的f -18标记。
C-X-C chemokine receptor 4 (CXCR4) is highly expressed in cancers, contributing to proliferation, metastasis, and a poor prognosis. The noninvasive imaging of CXCR4 can enable the detection and characterization of aggressive cancers with poor outcomes. Currently, no F-18-labeled CXCR4 positron emission tomography (PET) radiotracer has demonstrated imaging contrast comparable to [Ga-68]Ga-Pentixafor, a CXCR4-targeting radioligand. We, therefore, aimed to develop a high-contrast CXCR4-targeting radiotracer by incorporating a hydrophilic linker and trifluoroborate radioprosthesis to LY2510924, a known CXCR4 antagonist. A carboxy-ammoniomethyl-trifluoroborate (PepBF(3)) moiety was conjugated to the LY2510924-derived peptide possessing a triglutamate linker via amide bond formation to obtain BL08, whereas an alkyne ammoniomethyl-trifluoroborate (AMBF(3)) moiety was conjugated using the copper-catalyzed [3+2] cycloaddition click reaction to obtain BL09. BL08 and BL09 were radiolabeled with [F-18]fluoride ion using F-18-F-19 isotope exchange. Pentixafor was radiolabeled with [Ga-68]GaCl3. Side-by-side PET imaging and biodistribution studies were performed on immunocompromised mice bearing Daudi Burkitt lymphoma xenografts. The biodistribution of [F-18]BL08 and [18F]BL09 showed tumor uptake at 2 h postinjection (p.i.) (5.67 +/- 1.25%ID/g and 5.83 +/- 0.92%ID/g, respectively), which were concordant with the results of PET imaging. [F-18]BL08 had low background activity, providing tumor-to-blood, -muscle, and -liver ratios of 72 +/- 20, 339 +/- 81, and 14 +/- 3 (2 h p.i.), respectively. [F-18]BL09 behaved similarly, with ratios of 64 +/- 20, 239 +/- 72, and 17 +/- 3 (2 h p.i.), respectively. This resulted in high-contrast visualization of tumors on PET imaging for both radiotracers. [F-18]BL08 exhibited lower kidney uptake (2.2 +/- 0.5%ID/g) compared to [F-18]BL09 (7.6 +/- 1.0%ID/g) at 2 h p.i. [F-18]BL08 and [F-18]BL09 demonstrated higher tumor-to-blood, -muscle, and -liver ratios compared to [Ga-68]Ga-Pentixafor (18.9 +/- 2.7, 95.4 +/- 36.7, and 5.9 +/- 0.7 at 2 h p.i., respectively). In conclusion, [F-18]BL08 and [F-18]BL09 enable high-contrast visualization of CXCR4 expression in Daudi xenografts. Based on high tumor-to-organ ratios, [F-18]BL08 may prove a valuable new tool for CXCR4-targeted PET imaging with potential for translation. The use of a PepBF3 moiety is a new approach for the orthogonal conjugation of organotrifluoroborates for F-18-labeling of peptides.