PET Imaging of CXCR4 Expression Using [18F]AlF-NOTA-QHY-04 for Solid Tumors and Hematologic Malignancy

Introduction: C-X-C motif chemokine receptor 4 (CXCR4) is an important target for the diagnosis and treatment of a variety 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 both preclinical and pilot clinical studies.C-X-C motif chemokine receptor 4 (CXCR4) is an important target for the diagnosis and treatment of a variety 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 both preclinical and pilot clinical studies.

Methods: [¹⁸F]AlF-NOTA-QHY-04 was synthesized based on a potent CXCR4 peptide antagonist, and evaluated by cellular uptake, blocking and biolayer interferometry studies in vitro. The pharmacokinetics, biodistribution, and tumor imaging specificity of [¹⁸F]AlF-NOTA-QHY-04 were researched in tumor-bearing mice. [¹⁸F]AlF-NOTA-QHY-04 PET/CT (positron emission tomography/computed tomography) 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 of tumor sections from patients.

Results: [¹⁸F]AlF-NOTA-QHY-04 was prepared with a high radiolabeling yield and radiochemical purity. [¹⁸F]AlF-NOTA-QHY-04 exhibited good stability, high binding affinity and specificity for CXCR4 both in vitro and in vivo. NCI-H69 (small cell lung cancer, SCLC) tumor-bearing mice showed the highest tumor uptake of [¹⁸F]AlF-NOTA-QHY-04 on PET imaging except for Daudi lymphoma xenograft model, which was in accordance with the results of cellular and histological analyses. Similar results were observed in PET imaging of cancer patients (SUV_max for diffuse large B-cell lymphoma and SCLC, 11.10 ± 4.79 vs. 7.51 ± 3.01, P = 0.004), which were both significantly higher than that in other solid tumors (P < 0.05) and there was no difference among them. Significant higher T/N of [¹⁸F]AlF-NOTA-QHY-04 than [¹⁸F]FDG (62.55 ± 38.67 vs. 1.69 ± 0.22, P = 0.027) was found in 4 patients with primary brain tumors. Strong and positive correlations between percentage of CXCR4-positive staining of IHC and SUV_max, SUV_mean and SUV_peak (all P < 0.01) were recorded. Multicolor immunofluorescence staining indicated the high tracer uptake in patients is due to the high expression of CXCR4 in tumor cells, followed by macrophages infiltrated in the tumor microenvironment.

Conclusions: The CXCR4-targeted radiotracer [¹⁸F]AlF-NOTA-QHY-04 was successfully fabricated with favorable yield, high specificity and binding affinity to CXCR4. Preclinical and pilot clinical studies demonstrated its feasibility and potential application in precise diagnosis and CXCR4-targeted therapies 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.

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