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Selective PET imaging of CXCR4 using the Al18F-labeled antagonist LY2510924
Muriel Aline Spahn1, Tom Van Loy2, Sofie Celen3
1Radiopharmaceutical Research, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium.
Background:
[68Ga]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 Al18F-labeled radiotracer derived from LY2510924 for CXCR4-targeted imaging, leveraging the physical and logistical advantages of fluorine-18.
Methods:
We designed a CXCR4-specific radioprobe, [18F]AlF-NOTA-SC, based on LY2510924 by incorporating a triglutamate linker and NOTA chelator to enable Al18F-labeling. The in vitro CXCR4 affinity was assessed using cell-based binding assays. Subsequently, in vivo pharmacokinetics and tumor uptake of [18F]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.
Results:
Compared to Ga-PentixaFor, AlF-NOTA-SC demonstrated similar in vitro affinity for human CXCR4. [18F]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 [18F]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 (SUVmeanU87.CD4 = 0.04 ± 0.00 (n = 3); SUVmeanU87.CD4.CXCR4 = 3.04 ± 0.65 (n = 3); SUVmeanMM.1 S = 1.95 ± 0.11 (n = 3)). In a non-human primate, [18F]AlF-NOTA-SC accumulated in CXCR4 expressing organs, such as the spleen and bone marrow.
Conclusion:
[18F]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 18F-alternative to [68Ga]PentixaFor.
Insights
A new fluorine-18 radiotracer, [18F]AlF-NOTA-SC, targets C-X-C chemokine receptor type 4 (CXCR4) with high specificity. This tracer shows promising tumor uptake and may serve as an effective alternative to Gallium-68 labeled tracers for cancer imaging.
Area of Science:
- Nuclear Medicine
- Radiochemistry
- Oncology
Background:
- C-X-C chemokine receptor type 4 (CXCR4) is overexpressed in various cancers and inflammatory conditions.
- [68Ga]PentixaFor is a Gallium-68 labeled radiotracer used for detecting CXCR4 overexpression.
- Fluorine-18 offers physical and logistical advantages for radiotracer development.
Purpose of the Study:
- To develop a novel Al18F-labeled radiotracer for CXCR4-targeted imaging.
- To create a fluorine-18 alternative to [68Ga]PentixaFor, leveraging the benefits of 18F.
Main Methods:
- A CXCR4-specific radioprobe, [18F]AlF-NOTA-SC, was designed based on LY2510924, incorporating a triglutamate linker and NOTA chelator for Al18F-labeling.
- In vitro affinity was assessed using cell-based binding assays.
- In vivo pharmacokinetics, tumor uptake, and biodistribution were evaluated in mice and non-human primates using PET-MR.
Main Results:
- [18F]AlF-NOTA-SC demonstrated comparable in vitro affinity to [68Ga]PentixaFor for human CXCR4.
- The radiotracer was produced with good radiochemical yield and specific activity.
- Significant CXCR4-specific uptake was observed in xenografted tumors in mice, with minimal accumulation in non-target organs in naïve mice.
- Biodistribution in a non-human primate showed accumulation in CXCR4-expressing organs like the spleen and bone marrow.
Conclusions:
- [18F]AlF-NOTA-SC exhibits specific in vitro and in vivo uptake for CXCR4.
- The tracer demonstrates fast and persistent tumor accumulation, indicating its potential for clinical applications.
- [18F]AlF-NOTA-SC is a promising 18F-alternative to [68Ga]PentixaFor for CXCR4-targeted molecular imaging.
