Biological Evaluation of [18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma

Liping Lin; Xianhong Xiang; Shu Su; Shaoyu Liu; Ying Xiong; Hui Ma; Gongjun Yuan; Dahong Nie; Ganghua Tang

doi:10.3389/fchem.2021.630452

Biological Evaluation of [¹⁸F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma

Front Chem. 2021 Apr 16:9:630452. doi: 10.3389/fchem.2021.630452. eCollection 2021.

Authors

Liping Lin¹, Xianhong Xiang¹, Shu Su¹, Shaoyu Liu¹, Ying Xiong¹, Hui Ma¹, Gongjun Yuan¹, Dahong Nie^{1

2}, Ganghua Tang^{1

3}

Affiliations

¹ Department of Radiology Intervention and Medical Imaging, Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
² Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Nanfang PET Center, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Abstract

Purpose: N-(2-[¹⁸F]fluoropropionyl)-L-glutamate ([¹⁸F]FPGLU) for hepatocellular carcinoma (HCC) imaging has been performed in our previous studies, but its radiosynthesis method and stability in vivo need to be improved. Hence, we evaluated the synthesis and biological properties of a simple [¹⁸F]-labeled glutamate analog, [¹⁸F]AlF-1,4,7-triazacyclononane-1,4,7-triacetic-acid-2-S-(4-isothiocyanatobenzyl)-l-glutamate ([¹⁸F]AlF-NOTA-NSC-GLU), for HCC imaging. Procedures: [¹⁸F]AlF-NOTA-NSC-GLU was synthesized via a one-step reaction sequence from NOTA-NSC-GLU. In order to investigate the imaging value of [¹⁸F]AlF-NOTA-NSC-GLU in HCC, we conducted positron emission tomography/computed tomography (PET/CT) imaging and competitive binding of [¹⁸F]AlF-NOTA-NSC-GLU in human Hep3B tumor-bearing mice. The transport mechanism of [¹⁸F]AlF-NOTA-NSC-GLU was determined by competitive inhibition and protein incorporation experiments in vitro. Results: [¹⁸F]AlF-NOTA-NSC-GLU was prepared with an overall radiochemical yield of 29.3 ± 5.6% (n = 10) without decay correction within 20 min. In vitro competitive inhibition experiments demonstrated that the Na⁺-dependent systems $X_{AG}^{-}$ , B0⁺, ASC, and minor $X_{C}^{-}$ were involved in the uptake of [¹⁸F]AlF-NOTA-NSC-GLU, with the Na⁺-dependent system $X_{AG}^{-}$ possibly playing a more dominant role. Protein incorporation studies of the Hep3B human hepatoma cell line showed almost no protein incorporation. Micro-PET/CT imaging with [¹⁸F]AlF-NOTA-NSC-GLU showed good tumor-to-background contrast in Hep3B human hepatoma-bearing mouse models. After [¹⁸F]AlF-NOTA-NSC-GLU injection, the tumor-to-liver uptake ratio of [¹⁸F]AlF-NOTA-NSC-GLU was 2.06 ± 0.17 at 30 min post-injection. In vivo competitive binding experiments showed that the tumor-to-liver uptake ratio decreased with the addition of inhibitors to block the X_AG system. Conclusions: We have successfully synthesized [¹⁸F]AlF-NOTA-NSC-GLU as a novel PET tracer with good radiochemical yield and high radiochemical purity. Our findings indicate that [¹⁸F]AlF-NOTA-NSC-GLU may be a potential candidate for HCC imaging. Also, a further biological evaluation is underway.

Keywords: PET; [18F]AlF-NOTA-NSC-GLU; hepatocellular carcinoma; system XAG-; tumor imaging.