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20 February 2017, Volume 30 Issue 1

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Preparation and Biological Evaluation of ^99mTc Labeled Somatostatin Analogue ^99mTc-HYNIC-KE108

ZHANG Jian;WANG Ning;CHENG Wei-hua;LI Zhong-yong;WANG Xiao-jing

2017, 30(1):  1-8.  DOI: 10.7538/tws.2017.30.01.0001

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Most tumor cells overexpress somatostatin receptors. It is well known that somatostatin and its analogues can bind to somatostatin receptors specifically. Therefore, radionuclide-labeled somatostitin and its analogues may be used for the early diagnosis of somatostatin receptor positive tumours. In order to explore the feasibility of somatostatin analogues HYNIC-KE108 for somatostatin receptor positive tumor imaging, the new somatostatin analogue ^99mTc-HYNIC-KE108 was designed and synthesized. The lipid water partition coefficient and in vitro stability of the markers were determined. The biological studies were carried out in normal mice and also in tumor-bearing nude mice. The labelling yield of ^99mTc-HYNIC-KE108 was approximately 90% under the optimized conditions, and the radiochemical purity was more than 98% after Waters Oasis HLB colunm purification. The lipid-water partition coefficient of the marker LogP was 0.43±0.02 (n=3). The labelled complex showed satisfactory stability in vitro.  ^99mTc-HYNIC-KE108 displayed a rapid blood and metabolized by kidneys. Meanwhile, the substantial uptakes of radioactivity in stomach, lung and liver were observed. The biodistribution of the labeled compound in tumor-bearing mice was 1.14±0.91(%ID•g^-1) at 4 h after injection. There was high radioactivity uptake in tumor and rapid blood clearance, and thus high ratios of tumor to blood and muscle were obtained at 4 h post injection. The tumor-to-normal tissue ratio (T/NT) for blood, muscle and heart were 1.78, 8.14 and 3.35, respectively. All these results indicate that ^99mTc-HYNIC-KE108 is a novel promising candidate for somatostatin receptor positive tumor imaging.

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Synthesis and Bio-distribution of Three Carbon-11-Labeled Phenylethylamine Derivatives

HE Yu-lin;ZHANG Xiao-jun;LIU Jian;FU Hua-ping;LI Yun-gang;ZHANG Jin-ming

2017, 30(1):  9-15.  DOI: 10.7538/tws.2017.30.01.0009

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N-methylphenylethylamine, N-m-MeTyramine and N-P-MeTyramine were labeled with Carbon-11 by methylation of amino group. Biological distribution characteristics of the three radiolabeled compounds in Kunming mice were evaluated. Synthesis of ［¹¹C］-N-methylphenethylamine requires 30 minutes including HPLC separation time. The yield was 25% and the radiochemical purity was more than 98%. Synthesis of ［¹¹C］-m-MeTyramine required 25 minutes including HPLC separation time. The yield was 13% and the radiochemical purity was more than 97%. Synthesis of ［¹¹C］-P-MeTyramine required 25 minutes including HPLC separation time. The yield was 28% and the radiochemical purity was more than 98%. Distribution study showed that amount of the three marker uptaken by the target organism-myocardium, at each time point was smaller than that uptaken by non-target organs like lung, liver, spleen, kidney. Myocardial uptake was similar with that of muscle. After injection of the markers for 10 minutes, concentration of ［¹¹C］-N-methylphenethylamine in lung and liver was 2.08 and 2.94 times higher than that in heart, respectively. Concentration of ［¹¹C］-m-MeTyramine in lung and liver was 2.56, 2.76 higher than that in heart, respectively. Concentration of ［¹¹C］-P-MeTyramine in lung and liver was 1.85 and 5 higher than that in heart,respectively. Present results suggested that although synthetic methods of ¹¹C labeled N-methylphenylethylamine, N-m-MeTyramine and N-P-MeTyramine were simple, but the targeting in myocardium were poor and might not be suitable for myocardial perfusion imaging.

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Synthesis and Quality Control of the PET Radiotracer ¹¹C-Flumazenil

LI Qi-ming;JIN Rong-bing;WANG Fang-yang;TANG Yi;YAO Zhi-peng

2017, 30(1):  16-22.  DOI: 10.7538/tws.2017.30.01.0016

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To produce the radioligand ¹¹C-flumazenil at very high quality and specific radioactivity for routinely clinical imaging , the procedures for its synthesis and purification were developed with domestic PET-CM-3H-IT-I synthesis module, and ¹¹C-CH₃I was used as methylation agent. ¹¹C-CH₃I was first synthesized by liquid phase reaction, the synthesis conditions of radiotracer ¹¹C-flumazenil were studied ,which included the alkali strength, alkali equivalent, solvents, temperature and purification conditions for the product. The optimum conditions were that ¹¹C-CH₃I was bubbled through a reactor at room temperature , containing a DMF solution of 1 mg desmethylflumazenic precursor and 1 mg NaH, the reaction was conducted at 55 ℃ for 2 minutes. The reaction solution was first transferred to Semi-HPLC for purification, the mobile phase consisted of acetonitrile-acetic acid-water (30∶4∶66), the flow rate was 5.0 mL/min, then the crude product was purified by C-18 Solid-Extraction Purification(SEP), the product retained on SEP cartridge was eluted with 1 mL alcohol, the eluant was diluted with 6 mL sterile injection water, the dilute solution passed through sterile membrane to end-product. The radiochemical purity and specific radioactivity were measured by High Performance Liquid Chromatograph (HPLC) with the mobile phase of acetonitrile-acetic acid-water (30∶4∶66), and the column was ODS (250 mm×4.6 mm, 5 μm). The results showed that the total synthesis time was (26±2) minutes from ¹¹C-CO₂ to obtain ¹¹C-flumazenil injection solution, the synthesis yield of ¹¹C-flumazenil was (45±4)% (decay corrected, n=10), the radiochemical purity was over 99% at specific activity of 4.7 TBq/mmol, the radioactivity concentration was 370～550 MBq/mL. The injection solution was proved to be sterile and pyrogen free. The radiochemical yield was increased greatly by optimizing the reaction conditions ,¹¹C-flumazenil was synthesized from ¹¹C-CH₃I with domestic C-11 synthesis module, the quality and quantity of ¹¹C-flumazenil was confirmed to be suitable for clinic use.

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Modified Auto-synthesis and Clinical Trial of the ¹¹C-PIB as a Potential β-amyloid Imaging Agent

ZHANG Zheng-wei;ZHU Jian-hua;YAO Zhi-wen;GUAN Yi-hui;HUA Feng-chun

2017, 30(1):  23-28.  DOI: 10.7538/tws.2017.30.01.0023

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The auto-synthesis method was developed for the on-line preparation of amyloid-beta (Aβ) plaques image agent ¹¹C-PIB. A intermediate, ¹¹CH₃OTf, made from ¹¹CH₃ which was produced from ¹¹CO₂ with LAH/THF, was bubbled into 1.0 mg precursor 6-OH-BTA-0 butanone solution in salt-ice condition. The final crude product was then purified though prep-HPLC to get purified product. The human images were obtained in four cases of AD and 1 normal volunteer. The total synthesis process took about 35 minutes. The synthesis yield (EOS) was (25±5)% (not correct), the radiochemical purity over 98%, and the specific activity about 5.55 GBq/μmol. The modified automated preparation of ¹¹C-PIB was verified in producing ¹¹C-PIB of high radiochemical purity and synthesis yield in a short time. The results showed that this promising product could be used in clinical imaging.

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Automated Radiosynthesis and Bio-distribution of ［¹⁸F］Fluoromethyl Choline

LI Yan-peng;WEN Xin;CHENG Bin;XIE Xin-li;DU Xiao-guang;HAN Xing-min

2017, 30(1):  29-35.  DOI: 10.7538/tws.2017.30.01.0029

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To develop a rapid and automated synthetic method for making ［¹⁸F］Fluoromethyl choline （¹⁸F-FCH）, the automatic synthesis module from Sumitomo corporation was used to synthesize ¹⁸F-FCH, the bio-distribution in normal mice and the PET/CT imaging on pancreatic tumor xenograft murine models were also evaluated. CH₂Br₂ was used as precursor, intermediate product of ¹⁸FCH₂Br was produced by the gaseous reaction with ¹⁸F^-. Then, the ¹⁸FCH2OTf, more reactive ¹⁸F fluotomethylating agent than the ¹⁸FCH2Br, was converted on-line by passing ¹⁸FCH₂Br through a heated Ag-Triflate column. ¹⁸FC₂H₄SO₃CF₃ reacted with N, N-dimethylaminoethanol (DMAE) on SEP-PAK C-18 cartridge, followed by purification on SEP-PAK Accell CM cartridge. The ¹⁸F-FCH was intravenously injected into mice, the mice were sacrificed at 5,  10, 30, 60, 90, 120 minutes post injection respectively. The major organs were removed and weighed before radioactive γ-counting. PET/CT imaging was carried out at 10 minutes after injection of  ¹⁸F-FCH in nude mice xenografted with pancreatic cancer. The results showed that ［¹⁸F］fluorocholine was produced from ［¹⁸F］fluoride in overall radiochemical yields of （25±5）% (uncorrected, n=23) in 32 minutes, radiochemical purity was higher than 97%. The biodistribution datas showed high uptake in liver, kidney, low uptake in brain, lung, muscle and rapid clearance in blood. Most organs reached its radioactive peak within 5 minutes and then decreasing or in a relatively stable state. The bio-distribution of ¹⁸F-FCH was similar with the reported data of ¹¹C-choline. PET/CT imaging showed high accumulation in the kidney, liver and spleen, however, the uptake of ¹⁸F-FCH in the pancreatic cancer was very low. It has very low potential as a positive pancreatic cancer imaging agent. This new automated synthesis technique provides high and reproducible yields that could be dedicated for routine use.

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The ¹⁸F-FDG-(OAc)₄ Residual in ¹⁸F-FDG and its Bio-distribution in Mice

WANG Lei;ZHANG Xiao-jun;ZHOU Yan-li;ZHANG Jin-ming

2017, 30(1):  36-42.  DOI: 10.7538/tws.2017.30.01.0036

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To investigate the causes of ¹⁸F-FDG-(OAc)₄ residual in ¹⁸F-FDG and the discrepancy of bio-distributions between ¹⁸F-FDG-(OAc)₄ and ¹⁸F-FDG, ¹⁸F-FDG was prepared by hydrolysis on C-18 .The effect of NaOH dosage, elution rate, and eluent pH on ¹⁸F-FDG-(OAc)₄ residual ,the metabolism and biodistribution profiles of ¹⁸F-FDG-(OAc)₄ in mice were stutied. The results showed that insufficiency of NaOH was the main reason for ¹⁸F-FDG-(OAc)₄ residual, while the elution rate and the pH of the eluent posed no impact. After injecting ¹⁸F-FDG-(OAc)₄ 60 minutes, the partially hydrolyzed product and ¹⁸F-FDG-(OAc)₄ were found in metabolite of blood、urine and brain of the mice. The mice bio-distribution suggested that  the uptake of ¹⁸F-FDG-(OAc)₄ and ¹⁸F-FDG by organs followed the same pattern apart from muscle.

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Rapid Detection of Bacterial Endotoxin Content in ¹⁸F-FDG Injection

FU Hua-ping;ZHANG Xiao-jun;HE Yu-lin;ZHANG Jin-ming

2017, 30(1):  43-47.  DOI: 10.7538/tws.2017.30.01.0043

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The American Endosafe-PTS detector of bacterial endotoxin was used to detecte ⁸F-FDG injection, and the results were compared to traditional spectrophotometric determination. Meanwhile, the impacts on the content of bacterial endotoxin caused by new production and high radio-dose of ¹⁸F-FDG was also evaluated by PTS detection. The results showed that recovery rates were about 50% to 200%, detecting contents were smaller than 5 EU/mL, both of which conformed to the rules of ¹⁸F-FDG in Chinese Pharmacopeia. The detecting results were consistent between PTS and traditional spectrophotometric detection, which indicated the trustworthiness and reliability for PTS detecttion. The consistence before and after radiative decay of new production and high radiodose of ¹⁸F-FDG indicated that radiactive rays had no impacts on the content of bacterial endotoxin. The results reveal that PTS-based detection of bacterial endotoxin content is a rapid and effective approach for ¹⁸F-FDG injection.

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Technology Verification for Automated Synthesis Process of ¹⁸F-FMISO Based on Domestic Fluorine Multifunctional Module

YU Qian;LIU Ting-ting;LIANG Zhi-gang;CHEN Shu-an;PENG Cheng

2017, 30(1):  48-53.  DOI: 10.7538/tws.2017.30.01.0048

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1-H-1-(3-［¹⁸F］fluoro-2-hydroxypropyl)-2-nitroimidazole(¹⁸F-FMISO) is a special tumor hypoxia imaging agent for PET. Its PET/CT imaging has an important guiding significance on planning cancer radiotherapy target volume. ¹⁸F-FMISO was synthesized on domestic fluorine multifunctional automated synthesis apparatus. By  using 1-(2′-nitro-1′-imidazolyl)-2-O-tetrahydropyranyl-3-O-toluenesulphonyl-propanediol as the precursor, ¹⁸F-FMISO was obtained via two-step reactions, including the nucleophilic fluoration of the precursor and the acidic hydrolysis of the intermediate. To verify the feasibility, reliability and stability of the automated synthesis process, three continuous batches of ¹⁸F-FMISO were produced with optimized preparation process. The key parameters in the pilot production and the quality standard of the product were verified. The procedure could be completed within 40 minutes. The radiochemical yield and specific activity were higher than 45% (no decay corrected, n=5) and 3.7×10¹⁰ Bq/mmol. The radiochemical purity was more than 95% after three half-life, indicating its good stability. The automated synthesis process of ¹⁸F-FMISO is feasible. All the indicators for each batch of ¹⁸F-FMISO meet the quality standard and the requirements of clinical PET imaging.

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Progress of Preparation and Applications of No-Carrier-Added Radioiodinated MIBG

FAN Cai-yun;DENG Xin-rong;LUO Zhi-fu

2017, 30(1):  54-62.  DOI: 10.7538/tws.2017.30.01.0054

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Radioiodinated metaiodobenzylguanidine (MIBG) is an important diagnostic agent for oncology and cardiology, or as a targeted radiotherapeutic for neuroendocrine tumors. Commercial formulations of radioiodinated MIBG (carrier-added (c.a.) ［*I］MIBG) contain large mass amount of unlabeled MIBG, which is disadvantage to diagnosis or therapy with adverse effects in patients. High specific activity no-carrier-added radioiodinated MIBG ( n.c.a. ［*I］MIBG) has the advantage of lower risk of adverse effects and is more suitable for clinical diagnostic and therapy. Much importance was attached to the preparation and application of n.c.a. ［*I］MIBG, and great achievements had been made in the last 20 years. Here we considered the methods of preparation of n.c.a.［*I］MIBG, comparison of n.c.a. ［*I］MIBG and c.a. ［*I］MIBG in diagnostic and therapy, and the clinical status of n.c.a. ［*I］MIBG.

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Research Progress of Radiopharmaceuticals for Progesterone Receptor Targeted Breast Cancer Imaging

WU Xiao-wei;ZHANG Xian-zhong

2017, 30(1):  63-70.  DOI: 10.7538/tws.2017.30.01.0063

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Presently, several molecular imaging techniques including nuclear medicine imaging, magnetic resonance imaging, optical imaging and ultrasonic technology have been extensively used in clinic. Compared with other imaging techniques, nuclear medical imaging can not only display the metabolic, functional and morphological information of living subject, but also has the advantages of high sensitivity, quantitative research, and detecting lesions at earlier time. In this review, the recent progress of radiopharmaceuticals in the diagnosis of breast cancer by targeting to progesterone receptor was reviewed from the aspects of the single photon emission tomography and positron imaging agent.

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Research Progress in the Preparation of ¹⁸F-DOPA

JIA Li-na;ZHANG Lan

2017, 30(1):  71-77.  DOI: 10.7538/tws.2017.30.01.0071

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［¹⁸F］6-fluoro-3,4-dihydroxy-L-phenylalanine (¹⁸F-DOPA) has been known to be a useful radiotracer for neuropsychiatric diseases and brain malignancies, and it is also abundantly used for visualizing neuroendocrine tumors at present. However, its more widespread clinical use was hampered by the lack of a high specific activity, high yielding labeling method. This review mainly summarized new developments in the synthesis of ¹⁸F-DOPA with electrophilic reactions and nucleophilic substitution reactions in recent years. Among these, considerable advances in nucleophilic synthesis had been achieved by developing novel precursors and utilizing chiral phase-transfer catalysts (cPTC) mediated fluorinations allowing for the production of ¹⁸F-DOPA in high specific activity and high radiochemical yield.

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Positron Emission Radiometals ⁶⁴Cu, ⁶⁸Ga, ⁸⁶Y and ⁸⁹Zr Labeled PET Drugs

CHEN Wen;WEI Hong-yuan;ZHOU Zhi-jun;LUO Shun-zhong

2017, 30(1):  78-88.  DOI: 10.7538/tws.2017.30.01.0078

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Positron emission radiometals ⁶⁴Cu, ⁶⁸Ga, ⁸⁶Y and ⁸⁹Zr have different half lives and special biological properties, not only enrich the diversity of PET drugs, but also provide a new opportunity for the diagnosis and treatment of disease. In recent years, positron emission radiometals ⁶⁴Cu,  ⁶⁸Ga, ⁸⁶Y and ⁸⁹Zr have more and more applications in the medical diagnostics of PET (positron emission tomography). ⁶⁴Cu has already had a significant impact in cancer hypoxia imaging. ⁶⁸Ga is developing rapidly in the field of diagnosis of NET (Neuroendocrine tumor) tumor. ⁸⁹Zr and ⁸⁶Y are expected to play a role in the field of immunoPET and radioimmunotheray. This paper briefly reviews the research progress on the production and purification, solution coordination chemistry and applications of ⁶⁸Ga, ⁸⁶Y, ⁸⁹Zr and ⁶⁴Cu.