Selective PET imaging of CXCR4 using the Al 18 F-labeled antagonist LY2510924

• Published in: European journal of nuclear medicine and molecular imaging 2024-12
• Main Authors: Spahn, Muriel Aline, Loy, Tom Van, Celen, Sofie, Koole, Michel, Deroose, Christophe M, Cawthorne, Christopher, Vanduffel, Wim, Schols, Dominique, Bormans, Guy, Cleeren, Frederik
• Format: Article
• Language: English
• ISSN: 1619-7089

[ Ga]PentixaFor detects C-X-C chemokine receptor type 4 (CXCR4) overexpression in various malignancies, such as multiple myeloma and non-Hodgkin lymphomas, as well as in endocrine and inflammatory disorders. This study aimed to develop an Al F-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18. We designed a CXCR4-specific radioprobe, [ F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable Al F-labeling. The in vitro CXCR4 affinity was assessed using cell-based binding assays. Subsequently, in vivo pharmacokinetics and tumor uptake of [ F]AlF-NOTA-SC were assessed in naïve mice and mice with xenografts derived from U87.CD4/U87.CD4.CXCR4 and MM.1 S cells. Finally, biodistribution was determined in a non-human primate using PET-MR. Compared to Ga-PentixaFor, AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4. [ F]AlF-NOTA-SC was produced with a decay-corrected radiochemical yield of 21.0 ± 7.1% and an apparent molar activity of 16.4 ± 3.6 GBq/µmol. In [ F]AlF-NOTA-SC binding assays on U87.CD4.CXCR4 cells, the total bound fraction was 7.1 ± 0.5% (58% blocking by AMD3100). In naïve mice, the radiotracer did not accumulate in any organs; however, it showed a significant CXCR4-specific uptake in xenografted tumors (SUVmean  = 0.04 ± 0.00 (n = 3); SUVmean  = 3.04 ± 0.65 (n = 3); SUVmean  = 1.95 ± 0.11 (n = 3)). In a non-human primate, [ F]AlF-NOTA-SC accumulated in CXCR4 expressing organs, such as the spleen and bone marrow. [ F]AlF-NOTA-SC exhibited CXCR4-specific uptake in vitro and in vivo, with fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an F-alternative to [ Ga]PentixaFor.