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20 October 2018, Volume 31 Issue 5

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Full Automated Synthesis of ¹⁸F-FDOPA and Preliminary PET/CT Imaging

WEN Fuhua;ZHANG Zhanwen;Ma Hui;ZHANG Dake;TANG Ganghua

2018, 31(5):  269-275.  DOI: 10.7538/tws.2018.31.05.

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¹⁸F-fluoro-L-dihydroxyphenylalanine (¹⁸F-FDOPA) as a dopamine neurotransmitter imaging agent has been widely used for diagnosis and therapy evaluation of Parkinson's disease, brain tumors and neuroendocrine diseases with positron emission tomography (PET) imaging in clinical setting and research. To meet the increasing clinical demand in oncology and neurology, a routine protocol for the automated synthesis of ¹⁸F-FDOPA with a disposable cassette system on an imported multifunctional synthesizer was studied and discussed. ¹⁸F-FDOPA was automatically synthesized via a multiple-step reaction, including fluorination, reduction, iodization alkylation and hydrolysis, following purification by using a semi-preparative high-performance liquid chromatography (HPLC) system which was built in the multifunctional synthesizer. After HPLC purification, the purified ¹⁸F-FDOPA solution was collected and passed through a sterilizing filter into a collection bottle. The final ¹⁸F-FDOPA injection was obtained for quality control (QC) determination. The QC indexes of the final products were detected： the injection was colorless and transparent, pH value was at 4 to 5.5, radiochemical purity >98%, radionuclide purity >99%, specific activity >1.9 GBq/μmol, K_2.2.2 content <50 mg/L, methanol content <0.01%, alcohol content <0.01%, dichloromethane content <0.01 mg/L, dimethylformamide content <15 mg/L, bacterial endotoxin test <0.100 EU/mL, sterility test 0 cfu/mL,and abnormal toxicity test was negative. PET/CT imaging of rats was performed by intravenous injection of ¹⁸F-FDOPA half an hour after the intraperitoneal injection of carbidopa, PET/CT scan was performed after 100 min post-injection. The imaging of ¹⁸F-FDOPA showed symmetry high uptake in the bilateral striatum of normal rats. The decay-corrected radiochemical yield of ¹⁸F-FDOPA from the ¹⁸F-fluoride was (63.1±3.8)% (n=10) at the end of synthesis (EOS), the radiochemical purity was no less than 98%, and the total radiosynthesis time was within 80 min. The quality control results demonstrated that the quality indexes of the final injection solution met the relevant requirements of radiopharmaceutlcals, which were well-suited for clinical application. An efficient and high reproducible automatic method for the radiosynthesis of ¹⁸F-FDOPA with high radiochemical yields and good radiochemical purity is obtained and performed via a multi-step reaction on the multifunctional synthesizer.  ¹⁸F-FDOPA can be used for animal and human PET imaging.

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Distribution of Dopamine D2 Receptor PET Imaging Agent 18F-Fallypride in the Brain of Normal and Aged Rats

WANG Lizhen;XU Yuping;PAN Donghui;WANG Xinyu;YANG Runlin;YAN Junjie;SHENG Jie;HUANG Qianhuan;YANG Min

2018, 31(5):  276-282.  DOI: 10.7538/tws.2018.31.05.

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With the progress of population aging, the incidence of agerelated disease has greatly increased. The dopamine D2 receptor is closely related to the age-related diseases, such as PD and AD. The PET imaging of the dopamine D2 receptor can provide noninvasive, dynamic, early and quantitative information on the function of the brain. So we intend to prepare dopamine D2 receptor PET imaging agent ¹⁸F-Fallypride and to study the disturbution of the agent in the brain of normal and aged rats, further to explore the relationship between dopamine D2 receptor and senility. ¹⁸F-Fallypride was prepared by nucleophilic reaction. And the PET image was performed in aged and normal rats 15 minutes after injection of the agent .Striatums were delineated as the region of interesting (ROI), the standard uptake value (SUV) of which was calculated. PMOD was used for image fusion ,partition and quantitative analysis of standard uptake values of each brain area. After imaging, cardiac ventricle was perfused. The brain was obtained and frozen. The contour structure was observed by HE staining.The results showed that the labeling yield was over 95% and the radiochemical purity was higher than 98%. The stability was still over 95% 2 hours after incubation with PBS. The striatum uptake of ¹⁸F-Fallypride radioactivity in aged and normal rats 15 minutes after injection were (0.58±0.11)%ID/g, (0.39±0.14)%ID/g. The uptake of cortex cingulate, cortex insular, hypothalamus, olfactory, midbrain in normal rats ((0.120±0.012)%ID/g, (0.182±0.002)%ID/g, (0.111±0.002)%ID/g, (0.127±0.007)%ID/g, (0.083±0.012)%ID/g respectively) were inferior to aged rats ((0.154±0.013)%ID/g, （0.344±0.014）%ID/g, （0.244±0.019）%ID/g, （0.263±0.020）%ID/g, （0.216±0.012）%ID/g), which was displayed by PMOD. HE staining showed severe brain injury in elderly SD rats. Some neurons in the aged SD rats appeared acidophil change or nuclear fragmentation, accompanied by spongy deformation, lamellar or focal neuronal necrosis, and no obvious morphological changes. The relevance between dopamine D2 receptor and senility was demonstrated by PET imaging, which provided a basis for further research on the methodology of disease and pharmacodynamics research.

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Synthesis of 16-Epiestriol and its Radiolabeling Procedure

LIU Bingnan;XIONG Liping;JIANG Shende;YAO Shaobo

2018, 31(5):  283-290.  DOI: 10.7538/tws.2018.31.05.

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To explore novel synthetic routes of 16-epiestriol (Estra-1, 3, 5(10)-triene-3, 16β, 17β-triol), we used the estrone as the starting material. After some simple synthetic steps, 16-epiestriol was yielded. Identification and purity of intermediates in the synthetic routes were characterized by melting point and ¹H NMR spectrum analysis, respectively. In addition, the structure of 16-epiestriol was modified and radiolabeled with ¹⁸F-fluoride to yield ¹⁸F-FES. The corresponding quality control analysis of the injection were performed. The yield of two synthetic routes of 16-epiestriol were about 20% starting from estrone. Radiosynthesis of ¹⁸F-FES was finished in 60 minutes with a radiochemical yield of (30±4)% and radiochemical purity greater than 99%. The ¹⁸F-FES injection was colorless and clear and the pH value was 6.5-7.5. The specific activity of the injection saline was (1.75±0.25) Ci/μmol. In this study, 16-Epiestriol was yielded with a relatively high yield in two novel routes. ¹⁸F-FES was finally yielded after structure modification of 16-epiestriol and the corresponding radiolabeling procudure. The quality control results of the ¹⁸F-FES injection could meet the need in clinical examination.

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Preparation and Clinical Application of ¹⁸F-DCFPyL

ZHANG Xiaojun;FU Huaping;LI Yungang;LIU Jian;HE Yulin;LIU Yachao;XU Baixuan;ZHU Hong;WU Jiang;CUI Mengchao;ZHANG Jinming

2018, 31(5):  291-297.  DOI: 10.7538/tws.2018.31.05.

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¹⁸F-DCFPyL, a PSMA-based PET imaging agent for prostate cancer, was auto synthesized and evaluated. Following the direct nucleophilic heteroaromatic substitution with ［¹⁸F］fluoride at the ortho-position of precursor, the deprotection of the ester moieties of the intermediate with different acids was attempted to obtain a good hydrolysis yield. The biodistribution in normal NIH mice and PET/CT imaging for a patient with biochemical recurrence of prostate cancer were also performed. The results showed that no remarkable discrepancy of the hydrolysis efficiency was found among three kinds of acids, H₃PO₄, HCl and HI, which were 17.1%, 16.9% and 18.4%, respectively with a specific activity of 54 to 90 GBq/μmol. The highest levels of radioactivity in the NIH mice were observed in the kidneys. Meanwhile, the uptake of the tracer in the blood was declined rapidly and a low accumulation of the radio-tracer was observed in most of the other organs. ¹⁸F-DCFPyL PET imaging for a postoperative patient with biochemical recurrence of prostate cancer can detect small metastatic foci that can not be detected by the CT. ¹⁸F-DCFPyL was synthesized reliably and repeatedly by domestic synthesis module and it passed the quality control. It has satisfactory properties in vivo and is probably suitable for early diagnosis of prostate cancer and detection of lesions in patients with biochemical recurrence of prostate cancer.

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Automatic Synthesis of ¹⁸F-6-F-L-DOPA and its Application in Clinical PET Imaging

FU Huaping;ZHANG Xiaojun;MA Guangyu;LIU Jian;XU Xiaodan;XU Baixuan;ZHANG Jinming

2018, 31(5):  298-303.  DOI: 10.7538/tws.2018.31.05.

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¹⁸F-6-Fluoride-L-DOPA (¹⁸F-DOPA) has an important value in the imaging diagnosis of neuroendocrine tumors. In this study, we used homemade Fluoride-module to synthesis ¹⁸F-DOPA and evaluate its clinical imaging. ¹⁸F-DOPA was synthesized by direct nucleophilic reaction with 6-boric acid-dimethoxy-L-DOPA as precursor, Cu(OTf)₂(py)₄ as catalyst, and hydrolysis by hydriodic acid. Quality control and the in vitro stability were preformed. The ¹⁸F-DOPA was confirmed PET imaging of neuroendocrine neoplasms and control. It took 60 minutes from ¹⁸F ions to ¹⁸F-DOPA, no corrected efficiency was （10.0±2.3）% (n=6), radiochemistry purity was over 99%. It could got 7.4 GBq of ¹⁸F-DOPA once time. The trace of ascorbic acid or ethanol could prevent radiolysis of ¹⁸F-DOPA. The striatum was seen at ¹⁸F DOPA imaging. The radioactivity were mainly extracted through kidney and urine. A positive lesion in pancreatic in patient with neuroendocrine tumor. ¹⁸F-DOPA was synthesized by direct nucleophilic reaction with homemade Fluoride-module. It could got good repeatability and high quality for clinical used.

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Optimization of the Radiosynthesis of the Dopamine Transporter Imaging Agent of ¹¹C-β-CFT

LI Haifeng;XU Rengen;LI Yungang;CHEN Zhijun;ZHANG Xiaojun;ZHANG Jinming

2018, 31(5):  304-309.  DOI: 10.7538/tws.2018.31.05.

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The optimization for high synthesis yield was designed with ¹¹C-Triflate-CH₃I as methylation agent for dopamine transporter imaging agent of ¹¹C-β-CFT. The influence factors of the synthesis process were discussed, and the optimum synthetic conditions were established. In the paper, the study showed that the amount of precursor, the irradiation time, eluated condition, the reaction solvent etc could effect the synthetic efficiency. ¹¹C-β-CFT was automatic synthesized on PET-CM-3H-IT-Ⅰ with the optimum process conditions as the irradiation time 10-24 minutes, 0.5-1.0 g/L of precursor in 0.2 mL acetone: acetonitrile(1∶1, V∶V) and room temperature. We obtained a radiochemical yield of (76.93±6.49)% (n=76, ¹¹C-Triflate-CH₃ EOB). The radiochemical purity of final products were over 97%. The specific activities of final products were over （56.26±1.55） TBq/g. It took 16 minutes from ¹¹C-CO₂ to ¹¹C-β-CFT and the radio activity of ¹¹C-β-CFT were (8.07±1.94) GBq (n=76). By optimization of the technological conditions, the target product was suitable for clinical, the synthetic process was reliable and full automated, the product yield was improved and the residual problem of Sep-Pak C18 was resloved.

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Synthesis and Biological Evaluation of 3-O-(2-¹⁸F-fluoroethyl)-L-DOPA as A Potential PET Agent for Tumor Imaging

MA Jingxin;WU Zhou;JIANG Shende;WANG Hongliang;WU Zhifang

2018, 31(5):  310-317.  DOI: 10.7538/tws.2017.youxian.070

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As a complementary category to ¹⁸F-2-fluoro-2-deoxy-D-glucose (¹⁸F-FDG), radiolabeled amino acids have been successfully employed for tumor imaging. To overcome the limitations of preparation of ¹⁸F-FDOPA, we had designed and synthesized a new ¹⁸F-radiolabeled amino acid tracer 3-O-(2-¹⁸F-fluoroethyl)-L-DOPA (¹⁸F-FEDOPA). Briefly, ¹⁸F-FEDOPA was prepared from a direct nucleophilic substitution with ¹⁸F using the new precusor, N-(tert-butoxycarbonyl)-3-(3-(2-(tosyloxy)ethoxy)-4-(tert-butoxycarbonyloxy))-L-DOPA methyl ester. The ¹⁸F-fluorinated intermediate was purified via semi-preparative HPLC and hydrolyzed by 4 mol/L HCl. After neutralized with 2 mol/L NaOH, ¹⁸F-FEDOPA was obtained as injectable solution. The overall radiochemical yield of ¹⁸F-FEDOPA was (33±6)% (n=10, decay corrected) within 90 minutes of radiosynthesis time, and the specific activity was 55 GBq/μmol. The radiochemical purity of ¹⁸F-FEDOPA (at room temperature) at 0, 60, 120 and 240 minutes were 99.35%, 98.58%, 97.98% and 97.49%, respectively, which indicated the high in vitro stability. Bio-distribution study in healthy ICR mice showed rapid clearance of ¹⁸F-FEDOPA from kidneys and low uptake in most tissues especially in brain and heart. The radioactivity in brain and heart at 60 minutes postinjection of ¹⁸F-FEDOPA were（1.01±0.18）%ID/g and （0.90±0.24）%ID/g, respectively. And there was no obvious uptake change in bone over the 90 minutes. microPET/CT imaging was performed on S180-H22 tumor-bearing ICR mice, which showed high accumulation of ¹⁸F-FEDOPA in tumor tissue. Furthermore, the ratios of tumor to brain and tumor to heart for ¹⁸F-FEDOPA (H22/brain: 7.73±2.10, S180/brain: 4.62±1.52, H22/heart: 4.33±1.22, S180/heart: 2.59±0.30) were higher than those of ¹⁸F-FDG (H22/brain: 2.14±0.71, S180/brain: 2.14±0.71, H22/heart: 1.89±0.25, S180/heart: 1.56±0.30) at 60 minutes post-injection. All these results indicated that ¹⁸F-FEDOPA would be a potential amino acid tracer for tumors PET imaging.

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Chronic Methamphetamine Abuse and Brain Deficits Revealed by Neuroimaging

YANG Hongjie;HU Shu;GAO Zhou;JIA Shaowei

2018, 31(5):  318-325.  DOI: 10.7538/tws.2017.youxian.072

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Amphetamines (mainly MA and amphetamine) are the second most prevalent psychoactive substances. In recent years, the abuse and dependence of MA has also became increasingly serious in China. The abuse and dependence of MA has became a global public health problem, which not only has a serious social impact but also occupies a significant amount of medical resources. Despite treating MA out of order, the mortality and relapse rate remains very high. Chronic abuse of MA can cause change in regional cerebral blood flow, glucose metabolism, certain biochemical substances, and even local brain structures. This paper presents a brief overview of the imaging findings of brain anatomical and functional change caused by the abuse and dependence of MA, which will help us understand the mechanism of MA dependence better. By searching a large number of the latest literatures, the paper summarizes the brain anatomical and functional change caused by chronic MA abuse by SPECT-CT, PET-CT, MRI, fMRI and proton MRS. These modern neuroimaging techniques allow us to observe change in regional cerebral blood flow and glucose metabolism caused by the abuse and dependence of MA under physiological conditions, to investigate the involvement brain regions and nucleus and to detect some certain neurochemicals change by proton MRS. The combination of neuroimaging techniques allow us monitor the brain anatomical structure change and molecular level change, and many of these neural abnormalities were found to be linked with certain addiction related phenotypes, such as cognitive inflexibility, maladaptive decision-making and poor self-control. Those addiction-related phenotypes may influence treatment response. Those brain anatomical and functional change may represent novel therapeutic targets, and it will play an important role in clinicians' treatment decisions. The development of the advanced neuroimaging technology will provide a good opportunity for studing and further clarifing the mechanism of MA dependence.

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The Progress of Nuclear Nanomedicines

ZHANG Huaming;LUO Shunzhong;WEI Hongyuan

2018, 31(5):  326-334.  DOI: 10.7538/tws.2017.youxian.029

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This manuscript briefly summarized the progress in the last decade and predicted the development in the future of nano-radiopharmaceuticals. The major carrier materials for nanoparticle delivery are biomaterials such as liposomes, or biocompatible materials such as phosphates, hydroxyapatite. Currently, various radionuclides, such as ¹³¹I, ¹¹¹In, ¹²⁵I, ¹⁶⁶Ho, ¹⁷⁷Lu, ⁹⁰Y, ²²⁵Ac are extensively used clinically or in research for diagnostic or therapeutic purpose. The preparation methodology of nano-radiopharmaceuticals includes post-irradiation activation, encapsulation, adsorption and etc. Many pre-clinical trials showed that nano-radiopharmaceuticals had displayed good specificity on cancer diagnosis and treatment, thus had became an important research direction in the diagnosis and treatment of cancer and personalized medical care.