C-X-C 基序趋化因子受体 4 (CXCR4) 是癌症诊断和治疗的一个有吸引力的靶点。在这里，我们的目标是开发一种新的 CXCR4 靶向 PET 示踪剂，并通过临床前和试点临床研究研究 CXCR4 表达在各种癌症实体中无创成像的转化潜力。方法合成[ 18 F]AlF-NOTA-QHY-04，并通过体外细胞摄取、阻断和生物层干涉测量研究进行评估。在荷瘤小鼠中研究了药代动力学、生物分布和成像特异性。对55名患有不同类型癌症的患者进行了[18F]AlF-NOTA-QHY-04 PET/CT成像。通过患者组织病理学染色分析离体CXCR4表达与PET参数之间的相关性以及不同肿瘤中CXCR4表达特征。结果制备的[ 18 F]AlF-NOTA-QHY-04具有较高的放射性标记产率和放射化学纯度，对CXCR4表现出良好的稳定性、高结合亲和力和特异性。除Daudi淋巴瘤异种移植模型外，NCI-H69（小细胞肺癌，SCLC）荷瘤小鼠在PET成像上显示出最高的肿瘤摄取（4.98±0.98%ID/mL，P < 0.0001），这与Daudi淋巴瘤异种移植模型的结果一致细胞和组织学分析。弥漫性大B细胞淋巴瘤患者的肿瘤摄取最高（SUVmax，11.10±4.79），其次是SCLC患者（SUVmax，7.51±3.01），均显着高于其他实体瘤（P<0.05）。高级别胶质瘤的放射性示踪剂摄取显着高于低级别胶质瘤（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的肿瘤与正常脑的比率显着高于[18F]FDG（62.55±43.24 vs 1.70±0.25，P = 0.027）。记录了离体CXCR4表达和[ 18 F]AlF-NOTA-QHY-04摄取之间的正相关性（所有P<0.01）。多色免疫荧光染色表明，某些患者示踪剂的高摄取主要是由于肿瘤细胞中CXCR4的高表达，其次是巨噬细胞。结论 成功制备了CXCR4靶向放射性示踪剂[ 18 F]AlF-NOTA-QHY-04，收率良好，特异性高，与CXCR4结合亲和力强。临床前和试点临床研究证明了其在淋巴瘤、小细胞肺癌和神经胶质瘤精确诊断方面的可行性和潜在应用。 [18F]AlF-NOTA-QHY-04 PET/CT 还可以为脑肿瘤提供与 [18F]FDG PET/CT 的互补映射。© 作者。

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.© The author(s).