PET imaging of CXCR4 expression using [F]AlF-NOTA-QHY-04 for hematologic malignancy and solid tumors.

in Theranostics by Kai Cheng, Shijie Wang, Tianxin Liu, Jinli Pei, Shasha Wang, Jingru Liu, Kunlong Zhao, Yuxi Luo, Shengnan Xu, Jinming Yu, Jie Liu

TLDR

  • The study aimed to develop a new PET tracer that can help doctors diagnose cancer by imaging a protein called CXCR4. The tracer was tested in mice and then in people with different types of cancer. The results showed that the tracer worked well and could help doctors diagnose cancer more accurately. The tracer can also help doctors see where the cancer is located in the brain.

Abstract

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.[F]AlF-NOTA-QHY-04 was synthesized and evaluated by cellular uptake, blocking and biolayer interferometry studies. The pharmacokinetics, biodistribution, and imaging specificity were researched in tumor-bearing mice. [F]AlF-NOTA-QHY-04 PET/CT imaging was performed on 55 patients with different types of cancers. Correlations betweenCXCR4 expression and PET parameters, and CXCR4 expression characteristics in different tumors were analyzed by histopathological staining in patients.[F]AlF-NOTA-QHY-04 was prepared with high radiolabeling yield and radiochemical purity, exhibiting good stability, high binding affinity and specificity for CXCR4NCI-H69 (small cell lung cancer, SCLC) tumor-bearing mice showed the highest tumor uptake (4.98 ± 0.98%ID/mL,< 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 (SUV, 11.10 ± 4.79) followed by SCLC patients (SUV, 7.51 ± 3.01), which were both significantly higher than other solid tumors (< 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,= 0.005). Significant higher tumor-to-normal brain ratio of [F]AlF-NOTA-QHY-04 than [F]FDG was found in primary brain tumors (62.55 ± 43.24 vs 1.70 ± 0.25,= 0.027). Positive correlations betweenCXCR4 expression and [F]AlF-NOTA-QHY-04 uptake (all< 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.The CXCR4-targeted radiotracer [F]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. [F]AlF-NOTA-QHY-04 PET/CT can also provide a complementary mapping for brain tumors to [F]FDG PET/CT.

Overview

  • The study aimed to develop a new CXCR4-targeted PET tracer and investigate its translational potential for noninvasive imaging of CXCR4 expression in various cancer entities through preclinical and pilot clinical studies. The study synthesized and evaluated [F]AlF-NOTA-QHY-04 by cellular uptake, blocking and biolayer interferometry studies. The pharmacokinetics, biodistribution, and imaging specificity were researched in tumor-bearing mice. [F]AlF-NOTA-QHY-04 PET/CT imaging was performed on 55 patients with different types of cancers. Correlations betweenCXCR4 expression and PET parameters, and CXCR4 expression characteristics in different tumors were analyzed by histopathological staining in patients.

Comparative Analysis & Findings

  • [F]AlF-NOTA-QHY-04 showed the highest tumor uptake in NCI-H69 (small cell lung cancer, SCLC) tumor-bearing mice 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 (SUV, 11.10 ± 4.79) followed by SCLC patients (SUV, 7.51 ± 3.01), which were both significantly higher than other solid tumors (< 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,= 0.005). Significant higher tumor-to-normal brain ratio of [F]AlF-NOTA-QHY-04 than [F]FDG was found in primary brain tumors (62.55 ± 43.24 vs 1.70 ± 0.25,= 0.027). Positive correlations betweenCXCR4 expression and [F]AlF-NOTA-QHY-04 uptake (all< 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.

Implications and Future Directions

  • The study demonstrated the feasibility and potential application of [F]AlF-NOTA-QHY-04 in precise diagnosis for not only lymphoma but also SCLC and glioma. [F]AlF-NOTA-QHY-04 PET/CT can also provide a complementary mapping for brain tumors to [F]FDG PET/CT.
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