使用[18F] ALF-NOTA-QHY-04进行血液学恶性肿瘤和实体瘤的CXCR4表达的PET成像

C-X-C基序趋化因子受体4（CXCR4）是诊断和治疗癌症的有吸引力的靶标。在这里，我们旨在开发新的CXCR4靶向宠物示踪剂，并通过临床前和试验临床研究研究各种癌症实体中CXCR4表达无创成像的转化潜力。通过在体外通过细胞摄取，阻断和生物层干涉法研究来合成和评估方法[18F] ALF-NOTA-QHY-04。在肿瘤小鼠中研究了药代动力学，生物分布和成像特异性。 [18F]对55例不同类型的癌症患者进行了ALF-NOTA-QHY-04 PET/CT成像。通过患者的组织病理学染色分析了离体CXCR4表达与PET参数与CXCR4表达特征之间的相关性。结果[18F] Alf-Nota-Qhy-04是用高放射性标记的产量和放射化学纯度制备的，表现出良好的稳定性，高结合亲和力和CXCR4的特异性。 NCI-H69（小细胞肺癌，SCLC）含有肿瘤的小鼠在PET成像上显示出最高的肿瘤摄取（4.98±0.98％ID/ml，P <0.0001），除了Daudi淋巴瘤异种移植模型，这与细胞和组织学分析的结果一致。弥漫性大B细胞淋巴瘤患者的肿瘤摄取量最高（Suvmax，11.10±4.79），其次是SCLC患者（SUVMAX，7.51±3.01），它们都明显高于其他实体瘤（P <0.05）。高级神经胶质瘤的放射性示例摄取明显高于低级神经胶质瘤（3.13±0.58 vs. 1.18±0.51，p = 0.005）。在原发性脑肿瘤中发现[18F] Alf-Nota-Qhy-04的肿瘤与非正常比率高于[18F] FDG（62.55±43.24 vs 1.70±0.25，p = 0.027）。记录了离体CXCR4表达与[18F] Alf-Nota-Qhy-04摄取（所有p <0.01）之间的正相关。多色免疫荧光染色表明某些患者的示踪剂摄取高主要是由于肿瘤细胞中CXCR4的高表达，然后是巨噬细胞。结论CXCR4靶向的radiotracer [18F] Alf-Nota-Qhy-04成功制备了良好的产率，高特异性和与CXCR4的结合亲和力。临床前和试点临床研究表明，其可行性和潜在的应用在精确诊断中不仅对淋巴瘤，而且还用于SCLC和神经胶质瘤。 [18F] ALF-NOTA-QHY-04 PET/CT还可以为[18F] FDG PET/CT提供互补的映射。

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.