利用[18F]AlF-NOTA-QHY-04进行CXCR4表达的PET成像，用于血液系统恶性肿瘤及实体瘤

C-X-C基序趋化因子受体4（CXCR4）是癌症诊断与治疗的一个有吸引力的靶点。在本研究中，我们旨在开发一种新型CXCR4靶向的PET示踪剂，并通过临床前和试点临床研究，探讨其在多种癌症中的非侵入性CXCR4表达成像的转化潜力。方法：[18F]AlF-NOTA-QHY-04通过细胞摄取、阻断及生物层干涉测量（BLI）在体外进行评估。在肿瘤携带小鼠中研究其药代动力学、组织分布及成像特异性。在55名不同类型癌症患者中进行[18F]AlF-NOTA-QHY-04 PET/CT成像。通过组织病理染色分析患者的体外CXCR4表达与PET参数的相关性，以及不同肿瘤的CXCR4表达特性。结果：[18F]AlF-NOTA-QHY-04的放射性标记效率高，放射化学纯度优良，表现出良好的稳定性，高结合亲和力和特异性。NCI-H69（小细胞肺癌，SCLC）肿瘤负鼠显示最高的肿瘤摄取（4.98 ± 0.98%ID/mL，P < 0.0001），与细胞和组织学分析结果一致。弥漫性大B细胞淋巴瘤患者的肿瘤摄取最高（SUVmax，11.10 ± 4.79），其次为SCLC患者（SUVmax，7.51 ± 3.01），两者均显著高于其他实体瘤（P < 0.05）。高等级胶质瘤的示踪剂摄取显著高于低等级胶质瘤（3.13 ± 0.58对1.18 ± 0.51，P = 0.005）。在原发性脑肿瘤中，[18F]AlF-NOTA-QHY-04的肿瘤对正常脑组织比值显著高于[18F]FDG（62.55 ± 43.24对1.70 ± 0.25，P = 0.027）。组织外CXCR4表达与[18F]AlF-NOTA-QHY-04摄取呈正相关（全部P < 0.01）。多色免疫荧光染色显示，某些患者中高示踪剂摄取主要源于肿瘤细胞中高表达的CXCR4，其次为巨噬细胞。结论：成功制备了具有良好产率、高特异性和结合亲和力的CXCR4靶向放射示踪剂[18F]AlF-NOTA-QHY-04。临床前和试点临床研究表明其在淋巴瘤、SCLC及胶质瘤的精准诊断中具有潜在应用价值。该示踪剂的PET/CT还能为脑肿瘤提供[18F]FDG PET/CT的补充映射。

C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for the diagnosis and treatment of cancers. Here, we aimed to develop a new CXCR4-targeted PET tracer, and to investigate the translational potential for noninvasive imaging of CXCR4 expression in various cancer entities through preclinical and pilot clinical studies. Methods [18F]AlF-NOTA-QHY-04 was synthesized and evaluated by cellular uptake, blocking and biolayer interferometry studies in vitro. The pharmacokinetics, biodistribution, and imaging specificity were researched in tumor-bearing mice. [18F]AlF-NOTA-QHY-04 PET/CT imaging was performed on 55 patients with different types of cancers. Correlations between ex vivo CXCR4 expression and PET parameters, and CXCR4 expression characteristics in different tumors were analyzed by histopathological staining in patients. Results [18F]AlF-NOTA-QHY-04 was prepared with high radiolabeling yield and radiochemical purity, exhibiting good stability, high binding affinity and specificity for CXCR4. NCI-H69 (small cell lung cancer, SCLC) tumor-bearing mice showed the highest tumor uptake (4.98 ± 0.98%ID/mL, P < 0.0001) on PET imaging except for Daudi lymphoma xenograft model, which was consistent with the results of cellular and histological analyses. Patients with diffuse large B-cell lymphoma showed the highest tumor uptake (SUVmax, 11.10 ± 4.79) followed by SCLC patients (SUVmax, 7.51 ± 3.01), which were both significantly higher than other solid tumors (P < 0.05). The radiotracer uptake of high-grade gliomas is significantly higher than that of low-grade gliomas (3.13 ± 0.58 vs. 1.18 ± 0.51, P = 0.005). Significant higher tumor-to-normal brain ratio of [18F]AlF-NOTA-QHY-04 than [18F]FDG was found in primary brain tumors (62.55 ± 43.24 vs 1.70 ± 0.25, P = 0.027). Positive correlations between ex vivo CXCR4 expression and [18F]AlF-NOTA-QHY-04 uptake (all P < 0.01) were recorded. Multicolor immunofluorescence staining indicated the high tracer uptake in certain patients was mainly due to the high expression of CXCR4 in tumor cells, followed by macrophages. Conclusion The CXCR4-targeted radiotracer [18F]AlF-NOTA-QHY-04 was successfully prepared with favorable yield, high specificity and binding affinity to CXCR4. Preclinical and pilot clinical studies demonstrated its feasibility and potential application in precise diagnosis for not only lymphoma but also SCLC and glioma. [18F]AlF-NOTA-QHY-04 PET/CT can also provide a complementary mapping for brain tumors to [18F]FDG PET/CT.