Syntheses and Preliminary Evaluation of Dual Target PET Probe [¹⁸F]-NOTA-Gly3- E (2PEG4-RGD-WH701) for PET Imaging of Breast Cancer

Author(s):

Zijun Chen, Hao Fu, Hua Wu, Jinxiong Huang, Lanlin Yao, Xianzhong Zhang and Yesen Li*   Pages 1548 - 1557 ( 10 )

Abstract:

<P>Purpose: Tumor Necrosis Factor Receptor 1 (TNFR1) and integrin &#945;v&#946;3 receptor are overexpressed in breast cancer. We hypothesized that a peptide ligand recognizing both receptors in a single receptor-binding probe would be advantageous. Here, we developed a novel ¹⁸F-labeled fusion peptide probe [¹⁸F]-NOTA-Gly3- E(2PEG4-RGD-WH701) targeting dual receptors (TNFR1 and &#945;v&#946;3) and evaluated the diagnostic efficacy of this radioactive probe in both MDA-MB-231 and MCF-7 xenograft models in mice. </P><P> Methods: The NOTA-conjugated RGD-WH701 analog was radiolabeled with 18F using NOTA-AlF chelation method. We used two PEG4 molecules and Glutamic acid (Glu) to covalently link c(RGDyK) with WH701. Gly3 was also added to further improve the water solubility and pharmacokinetic properties of the probe. The expression of TNFR1 and Integrin &#945;v&#946;3 in MCF-7 and MDA-MB-231 cells was detected by western blot analysis and immunofluorescence staining. The tumor-targeting characteristics of [¹⁸F]-NOTA-Gly3-E(2PEG4-RGDWH701) were assessed in nude mice bearing MDA-MB-231 and MCF-7 xenografts. </P><P> Results: HPLC analysis of the product NOTA-G3-E (2P4-RGD-WH701) revealed a purity >95%. The yield after attenuation correction was approximately 33.5%±2.8% (n=5), and the radiochemical purity was above 95%. The MDA-MB-231 tumor uptake of [¹⁸F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.14±0.14%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [¹⁸F]-NOTA-RGD and [¹⁸F]- NOTA-WH701 in MDA-MB-231 xenografts was 0.96±0.13%ID/g and 0.93±0.28%ID/g, respectively. The MCF-7 tumor uptake of [¹⁸F]-NOTA-Gly3-E(2PEG4-RGD-WH701) was 1.22±0.11%ID/g, as measured by PET at 40min postinjection (p.i.). In comparison, the tumor uptake of [¹⁸F]-NOTA-RGD and [¹⁸F]-NOTA-WH701 in MCF-7 xenografts was 0.99±0.18%ID/g and 0.57±0.08%ID/g, respectively. </P><P> Conclusion: [¹⁸F]AlF-NOTA-Gly3-E(2PEG4-RGD-WH701) was successfully synthesized and labeled with ¹⁸F. The results from the microPET/CT and biodistribution studies of [¹⁸F]AlF-NOTA-Gly3-E(2PEG4-RGDWH701) showed that the tracer could specifically target TNFR1 and integrin &#945;v&#946;3 receptors.</P>

Keywords:

¹⁸F labeling, peptides, TNFR1, &#945;v&#946;3 receptors, dual target, PET imaging.

Affiliation:

Medical College of Xiamen University, Xiamen University, Xiamen, Medical College of Xiamen University, Xiamen University, Xiamen, Department of Nuclear Medicine & Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Department of Nuclear Medicine & Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen, Medical College of Xiamen University, Xiamen University, Xiamen, Center for Molecular Imaging and Translational Medicine, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, Department of Nuclear Medicine & Minnan PET Center, Xiamen Cancer Hospital, The First Affiliated Hospital of Xiamen University, Teaching Hospital of Fujian Medical University, Xiamen

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