2917 - Preclinical Evaluation and Pilot Clinical Study of [¹⁸F]AlF-NOTA-QHY-04 for PET Imaging of CXCR4 Expression in Hematologic Malignancy and Solid Tumors

S. Xu¹, K. Cheng^1,2, T. Liu^1,3, J. Yu⁴, and J. Liu¹; ¹Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, ²Department of PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, ³Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China, ⁴Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China

Purpose/Objective(s): 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 both preclinical and pilot clinical studies. Materials/

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 imaging was performed on 55 patients with 8 different types of cancer. 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 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 consistent 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 other solid tumors (P < 0.05). 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 primary brain tumors. 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 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.