Selective PET imaging of CXCR4 using the AlF-labeled antagonist LY2510924.

in European journal of nuclear medicine and molecular imaging by Muriel Aline Spahn, Tom Van Loy, Sofie Celen, Michel Koole, Christophe M Deroose, Christopher Cawthorne, Wim Vanduffel, Dominique Schols, Guy Bormans, Frederik Cleeren

TLDR

  • The study developed an AlF-labeled radiotracer, [F]AlF-NOTA-SC, for CXCR4-targeted imaging with fluorine-18, showing promising in vitro and in vivo results.

Abstract

[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 AlF-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 AlF-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 anF-alternative to [Ga]PentixaFor.

Overview

  • The study aimed to develop an AlF-labeled radiotracer for CXCR4-targeted imaging using fluorine-18, leveraging its physical and logistical advantages.
  • The radiotracer, [F]AlF-NOTA-SC, was designed based on LY2510924, incorporating a triglutamate linker and NOTA chelator for AlF-labeling.
  • The study examined the in vitro CXCR4 affinity and in vivo pharmacokinetics, tumor uptake, and biodistribution of [F]AlF-NOTA-SC.

Comparative Analysis & Findings

  • [F]AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4 as Ga-PentixaFor.
  • In vivo, [F]AlF-NOTA-SC showed CXCR4-specific uptake in xenografted tumors and accumulated in CXCR4-expressing organs in a non-human primate.
  • The radiotracer exhibited fast and persistent tumor accumulation, making it a strong candidate for clinical translation as an F-alternative to [Ga]PentixaFor.

Implications and Future Directions

  • The study paves the way for the development of [F]AlF-NOTA-SC as a potential imaging agent for clinical translation.
  • Future studies will focus on further optimizing the radiotracer's affinity and pharmacokinetics, as well as exploring its potential for imaging various CXCR4-expressing pathologies.
  • The use of fluorine-18 could offer advantages over gallium-68 in terms of logistics and reduced costs, making [F]AlF-NOTA-SC a promising alternative for CXCR4-targeted imaging.
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