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Theranostics 2011; 1:220-229. doi:10.7150/thno/v01p0220 This volume Cite

Research Paper

¹⁸F-Labeled GRPR Agonists and Antagonists: A Comparative Study in Prostate Cancer Imaging

Min Yang^1,2*, Haokao Gao^{2, 3}*, Yaru Zhou⁴, Ying Ma², Qimeng Quan², Lixin Lang², Kai Chen², Gang Niu², Yongjun Yan^2✉, Xiaoyuan Chen^2✉

1. Key Laboratory of Nuclear Medicine, Ministry of Health, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, Jiangsu, 214063, China
2. Laboratory of Molecular Imaging and Nanomedicine (LOMIN), National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH), Bethesda, MD 20892, USA
3. Department of Cardiology, Xijing Hospital, the Fourth Military Medical University, Xi'an, 710032, China
4. Department of Endocrinology, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, 050051, China
* These authors contributed equally in this work.

✉ Corresponding author: Email: shawn.chengov (X.C.); yyan26edu (Y. Y)

Abstract

Radiolabeled bombesin analogs are promising probes for cancer imaging of gastrin-releasing peptide receptor (GRPR). In this study, we developed ¹⁸F-labeled GRPR agonists and antagonists for positron emission tomography (PET) imaging of prostate cancer. GRPR antagonists ATBBN (D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH₂CH₃) and MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-D-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH₂CH₃), and agonists AGBBN (Gln-Trp-Ala-Val-Gly-His-Leu-MetNH₂) and MAGBBN (Gly-Gly-Gly-Arg-Asp-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-MetNH₂) were radiolabeled with ¹⁸F via 4-nitrophenyl 2-¹⁸F-fluoropropionate. The in vitro receptor binding, cell uptake, and efflux properties of the radiotracers were studied on PC-3 cells. An in vivo PET study was performed on mice bearing PC-3 tumors. Direct ¹⁸F-labeling of known GRPR antagonist ATBBN and agonist AGBBN did not result in good tumor targeting or appropriate pharmacokinetics. Modification was made by introducing a highly hydrophilic linker Gly-Gly-Gly-Arg-Asp-Asn. Higher receptor binding affinity, much higher cell uptake and slower washout were observed for the agonist ¹⁸F-FP-MAGBBN over the antagonist ¹⁸F-FP-MATBBN. Both tracers showed good tumor/background contrast, with the agonist ¹⁸F-FP-MAGBBN having significantly higher tumor uptake than the antagonist ¹⁸F-FP-MATBBN (P < 0.01). In conclusion, Gly-Gly-Gly-Arg-Asp-Asn linker significantly improved the pharmacokinetics of the otherwise hydrophobic BBN radiotracers. ¹⁸F-labeled BBN peptide agonists may be the probes of choice for prostate cancer imaging due to their relatively high tumor uptake and retention as compared with the antagonist counterparts.

Keywords: gastrin-releasing peptide receptor (GRPR), bombesin (BBN), agonist, antagonist, positron emission tomography (PET), ¹⁸F

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