Radiosynthesis and biological evaluation of N-(2-[18F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine as a PET tracer for oncologic imaging

Abstract

Introduction: Several ¹¹C and ¹⁸F labeled 3,4-dihydroxy-l-phenylalanine (l-DOPA) analogues have been used for neurologic and oncologic diseases, especially for brain tumors and neuroendocrine tumors PET imaging. However, ¹⁸F-labeled N-substituted l-DOPA analogues have not been reported so far. In the current study, radiosynthesis and biological evaluation of a new ¹⁸F-labeled l-DOPA analogue, N-(2-[¹⁸F]fluoropropionyl)-3,4-dihydroxy-l-phenylalanine ([¹⁸F]FPDOPA) for tumor PET imaging are performed.

Methods: The synthesis of [¹⁸F]FPDOPA was via a two-step reaction sequence from 4-nitrophenyl-2-[¹⁸F]fluoropropionate ([¹⁸F]NFP). The biodistribution of [¹⁸F]FPDOPA was determined in normal Kunming mice. In vitro competitive inhibition and protein incorporation experiments were performed with SPC-A-1 lung adenocarcinoma cell lines. PET/CT studies of [¹⁸F]FPDOPA were conducted in C6 rat glioma and SPC-A-1 human lung adenocarcinoma and H460 human large cell lung cancer-bearing nude mice.

Results: [¹⁸F]FPDOPA was prepared with a decay-corrected radiochemical yield of 28±5% and a specific activity of 50±15GBq/μmol (n=10) within 125min. In vitro cell experiments showed that [¹⁸F]FPDOPA uptake in SPC-A-1 cells was primarily transported through Na⁺-independent system L, with Na⁺-dependent system B^0,+ and system ASC partly involved in it. Biodistribution data in mice showed that renal-bladder route was the main excretory system of [¹⁸F]FPDOPA. PET imaging demonstrated intense accumulation of [¹⁸F]FPDOPA in several tumor xenografts, with (8.50±0.40)%ID/g in C6 glioma, (6.30±0.12)%ID/g in SPC-A-1 lung adenocarcinoma, and (6.50±0.10)%ID/g in H460 large cell lung cancer, respectively.

Conclusion: A novel N-substituted ¹⁸F-labeled L-DOPA analogue [¹⁸F]FPDOPA is synthesized and evaluated in vitro and in vivo. The results support that [¹⁸F]FPDOPA seems to be a potential PET tracer for tumor imaging, especially be a better potential PET tracer than [¹⁸F]fluoro-2-deoxy-d-glucose ([¹⁸F]FDG) for brain tumor imaging.

Keywords: Biologic evaluation; Positron emission tomography; Tumor imaging; [(18)F]FPDOPA.