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Brown G, Soloviev D, Lewis DY. Radiosynthesis and Analysis of (S)-4-(3-[ 18F]Fluoropropyl)-L-Glutamic Acid. Mol Imaging Biol 2023; 25:586-595. [PMID: 36525163 PMCID: PMC10172245 DOI: 10.1007/s11307-022-01793-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Revised: 11/23/2022] [Accepted: 11/23/2022] [Indexed: 12/23/2022]
Abstract
PURPOSE (S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid ([18F]FSPG) is an L-glutamate derivative used as a PET biomarker to assess intracellular redox status in vivo through targeting of the cystine/glutamate antiporter protein, xc- transporter. In this report, we describe a radiosynthesis of [18F]FSPG for use in PET studies that address specific challenges in relation to the radiotracer purity, molar activity, and quality control testing methods. PROCEDURES The radiosynthesis of [18F]FSPG was performed using a customised RNPlus Research automated radiosynthesis system (Synthra GmbH, Hamburg, Germany). [18F]FSPG was labelled in the 3-fluoropropylmoiety at the 4-position of the glutamic acid backbone with fluorine-18 via substitution of nucleophilic [18F]fluoride with a protected naphthylsulfonyloxy-propyl-L-glutamate derivative. Radiochemical purity of the final product was determined by radio HPLC using a new method of direct analysis using a Hypercarb C18 column. RESULTS The average radioactivity yield of [18F]FSPG was 4.2 GBq (range, 3.4-4.8 GBq) at the end of synthesis, starting from 16 GBq of [18F]fluoride at the end of bombardment (n = 10) in a synthesis time of 50 min. The average molar activity and radioactivity volumetric concentration at the end of synthesis were 66 GBq µmol-1 (range, 48-73 GBq µmol-1) and 343-400 MBq mL-1, respectively. CONCLUSION Stability tests using a 4.6 GBq dose with a radioactivity volumetric concentration of 369 MBq mL-1 at the end of synthesis showed no observable radiolysis 3 h after production. The formulated product is of high radiochemical purity (> 95%) and higher molar activity compared to previous methods and is safe to inject into mice up to 3 h after production.
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Affiliation(s)
- Gavin Brown
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
| | - Dmitry Soloviev
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK
| | - David Y Lewis
- Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow, G61 1BD, UK.
- School of Cancer Sciences, University of Glasgow, Glasgow, G611QH, UK.
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Lin L, Xiang X, Su S, Liu S, Xiong Y, Ma H, Yuan G, Nie D, Tang G. Biological Evaluation of [ 18F]AlF-NOTA-NSC-GLU as a Positron Emission Tomography Tracer for Hepatocellular Carcinoma. Front Chem 2021; 9:630452. [PMID: 33937189 PMCID: PMC8085524 DOI: 10.3389/fchem.2021.630452] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/23/2021] [Indexed: 12/29/2022] Open
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 XAG-, B0+, ASC, and minor XC- were involved in the uptake of [18F]AlF-NOTA-NSC-GLU, with the Na+-dependent system XAG- 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 XAG 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.
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Affiliation(s)
- Liping Lin
- 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
| | - Xianhong Xiang
- 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
| | - Shu Su
- 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
| | - Shaoyu Liu
- 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
| | - Ying Xiong
- 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
| | - Hui Ma
- 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
| | - Gongjun Yuan
- 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
| | - Dahong Nie
- 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.,Department of Radiotherapy, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ganghua Tang
- 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.,Nanfang PET Center, Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Sun A, Liu S, Tang X, Pan Q, Zhang Z, Ma H, Nie D, Tang C, Tang G. N-(2-18F-fluoropropionyl)-l-glutamate as a potential oncology tracer for PET imaging of glioma. Appl Radiat Isot 2021; 168:109530. [PMID: 33285464 DOI: 10.1016/j.apradiso.2020.109530] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/16/2020] [Accepted: 11/20/2020] [Indexed: 10/22/2022]
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Tang C, Pan Q, Gao S, Sun A, Wen F, Tang G. Excitatory glutamate transporter EAAC1 as an important transporter of N-(2-[ 18F]fluoropropionyl)-L-glutamate in oncology PET imaging. Nucl Med Biol 2020; 84-85:55-62. [PMID: 32066035 DOI: 10.1016/j.nucmedbio.2020.02.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 01/24/2020] [Accepted: 02/09/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION We have reported that N-(2-[18F]fluoropropionyl)-L-glutamate ([18F]FPGLU) was a potential amino acid tracer for tumor imaging with positron emission tomography (PET). In this study, the relationship between glutamate transporter excitatory amino acid carrier 1 (EAAC1) expression and [18F]FPGLU uptake in rat C6 glioma cell lines and human SPC-A-1 lung adenocarcinoma cell lines was investigated. METHODS The uptake of [18F]FPGLU was assessed in ATRA-treated and untreated C6 cell lines, and also in EAAC1 knock-down SPC-A-1(shRNA) cells and SPC-A-1(NT) control cells. PET imaging of [18F]FPGLU was performed on the SPC-A-1 and SPC-A-1 (shRNA)-bearing mice models. RESULTS The uptake of [18F]FPGLU in C6 cells increased significantly after induced by ATRA for 24, 48, and 72 h, which was closely related to expression of EAAC1 in C6 cells (R2 = 0.939). Compared with the SPC-A-1(NT) control cells, the uptake of [18F]FPGLU on EAAC1 knock-down SPC-A-1(shRNA) cells significantly decreased to 64.0%. Moreover, the uptake of [18F]FPGLU in EAAC1 knock-down SPC-A-1(shRNA) xenografts was significantly lower than that in SPC-A-1 xenografts, with tumor/muscle ratios of 3.01 vs. 1.67 at 60 min post-injection of [18F]FPGLU. CONCLUSION The transport mechanism of [18F]FPGLU in glioma C6 and lung adenocarcinoma SPC-A-1 cell lines mainly involves in glutamate transporter EAAC1. EAAC1 is an important transporter of N-(2-[18F]fluoropropionyl)-L-glutamate in oncologic PET imaging.
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Affiliation(s)
- Caihua Tang
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China; Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qiyong Pan
- Department of Nuclear Medicine, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China
| | - Siyuan Gao
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Aixia Sun
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Fuhua Wen
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ganghua Tang
- Nanfang PET Center and Department of Nuclear Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application, Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China.
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Lu RC, She B, Gao WT, Ji YH, Xu DD, Wang QS, Wang SB. Positron-emission tomography for hepatocellular carcinoma: Current status and future prospects. World J Gastroenterol 2019; 25:4682-4695. [PMID: 31528094 PMCID: PMC6718031 DOI: 10.3748/wjg.v25.i32.4682] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 06/30/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality worldwide. Various imaging modalities provide important information about HCC for its clinical management. Since positron-emission tomography (PET) or PET-computed tomography was introduced to the oncologic setting, it has played crucial roles in detecting, distinguishing, accurately staging, and evaluating local, residual, and recurrent HCC. PET imaging visualizes tissue metabolic information that is closely associated with treatment. Dynamic PET imaging and dual-tracer have emerged as complementary techniques that aid in various aspects of HCC diagnosis. The advent of new radiotracers and the development of immuno-PET and PET-magnetic resonance imaging have improved the ability to detect lesions and have made great progress in treatment surveillance. The current PET diagnostic capabilities for HCC and the supplementary techniques are reviewed herein.
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Affiliation(s)
- Ren-Cai Lu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Bo She
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Wen-Tao Gao
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Yun-Hai Ji
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Dong-Dong Xu
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
| | - Quan-Shi Wang
- Nanfang PET Center, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Shao-Bo Wang
- PET-CT Center, the First People’s Hospital of Yunnan Province, Kunming 650032, Yunnan Province, China
- Yunnan Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming 650093, Yunnan Province, China
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Zhao J, Wang YL, Li XB, Gao SY, Liu SY, Song YK, Wang JY, Xiong Y, Ma H, Jiang L, Yang ZY, Tang GH, Chu JP. Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging. CONTRAST MEDIA & MOLECULAR IMAGING 2018; 2018:8439162. [PMID: 30670934 PMCID: PMC6317094 DOI: 10.1155/2018/8439162] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 10/15/2018] [Accepted: 10/24/2018] [Indexed: 01/15/2023]
Abstract
PURPOSES Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. PROCEDURES [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). RESULTS [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. CONCLUSIONS Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.
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Affiliation(s)
- Jing Zhao
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yu-liang Wang
- Department of Radiology, Shenzhen City Nanshan District People's Hospital, Shenzhen 518000, China
| | - Xin-bei Li
- Department of Radiology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, China
| | - Si-yuan Gao
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application PET-CT Center and Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Shao-yu Liu
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application PET-CT Center and Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Yu-kun Song
- Department of Radiology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China
| | - Jing-yan Wang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Ying Xiong
- Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Hui Ma
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application PET-CT Center and Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Li Jiang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Zhi-yun Yang
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Gang-hua Tang
- Guangdong Engineering Research Center for Medical Radiopharmaceuticals Translational Application PET-CT Center and Department of Nuclear Medicine, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Jian-ping Chu
- Department of Radiology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
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