正电子发射断层（PET）显像剂~(18)F-Fethypride化学合成、放射标记及生物学评价
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摘要
正电子发射计算机断层显像-计算机断层成像(positron emission tomography-computed tomography，PET/CT)，是目前临床应用最广泛的分子影像学检测设备之一。它实现了医学影像学从解剖结构变化向功能代谢变化的根本转变，PET/CT具有灵敏、特异、定位精确等特点，可以无创、定量、动态监测正电子核素标记的放射性药物在体内的分布，从分子水平反映活体内生理、生化改变，是理想的药物筛选平台。正电子放射性药物的选择是PET/CT成像的基础和关键。
帕金森氏病是三大常见的神经系统变性疾病之一，是一种慢性、隐袭性疾病，多见于老年人。帕金森氏病具有高度异质性，没有特异的诊断方法，主要依靠病史、临床症状和体征进行诊断，部分临床症状不典型或无症状的患者诊断更加困难。早期患者通过药物治疗大多可很好地控制症状，至疾病中、晚期由于对药物反应差，症状得不到控制，可出现全身僵硬，生活不能自理，严重影响生活质量，因此早诊断、早治疗显得尤为重要。
随着分子核医学迅速发展和新的正电子药物不断开发，针对帕金森氏病已经研发出多种特异的正电子放射性显像剂，通过PET/CT扫描，可以在解剖结构发生改变之前，从代谢和功能显像方面及时发现异常变化，从而达到早期诊断、及时治疗的目的。
1.目的
自行设计、研发一种新型的PET/CT显像剂18F-Fethypride，用于诊断帕金森氏病。对前体化合物合成中的每种产物进行核磁共振和高分辨质谱表征分析，以确定合成的是目标产物；探索放射性18Fˉ标记方法及最适反应条件，并对终产物进行一系列质量控制；对正电子放射性显像剂18F-Fethypride进行临床前急性毒性实验、稳定性实验、生物学分布实验和药代动力学实验，探讨18F-Fethypride临床应用的可行性。
2.方法
2.1以香草酸甲酯为原料，经7步常规反应和1步放射性18Fˉ标记合成一种新型的具有潜在应用前景的PET/CT显像剂18F-Fethypride，该化合物具有合成方法简单，原料价廉、易得，而且氮上的取代基还可以做进一步优化等优点。
2.2正电子放射性药物18F-Fethypride质量控制
2.2.1澄清度检测：通过比浊法检测18F-Fethypride溶液的澄清度，不超过0.5号浊度标准液的浊度为澄清，即合格。
2.2.2pH值检测：pH试纸检测18F-Fethypride溶液的pH值。
2.2.3放射化学纯度检测：用高效液相色谱法(HPLC)和薄层色谱法(TLC)检测18F-Fethypride溶液的放射化学纯度。
2.2.4细菌内毒素检测：用鲎试剂法检测18F-Fethypride溶液的细菌内毒素，细菌内毒素含量<10EU/ml，判定合格。
2.2.5无菌实验：18F-Fethypride溶液分别接种于2种不同培养基，放置不同温度培养14天后，各管培养基均无杂菌生长，判定合格。
2.2.6异常毒性实验：包括小鼠实验和豚鼠实验，将不同剂量的放射性药物18F-Fethypride腹腔注射受试动物，观察7天，观察期间动物应全部健存，无异常反应，到期后每只体重应增加，则供试品判定合格。
2.2.7氨基聚醚(K2.2.2)含量测定：分光光度法测定18F-Fethypride溶液中K2.2.2的含量，K2.2.2含量不得超过25μg/ml，判定合格。
2.3脂水分配系数测定
用γ-计数器分别测定放射性药物18F-Fethypride在正丁醇相和水相的放射性计数，两者计数比值的对数为脂水分配系数(Log P)。
2.4稳定性实验将18F-Fethypride溶液室温静置，分别于放射性标记后60min、90min、120min、180min、240min、300min测定放射性化学纯度并进行分析，评价18F-Fethypride溶液的稳定性，放化纯度应不低于90%。
2.5急性毒性实验
小鼠尾静脉注射不同浓度的18F-Fethypride溶液，观察7天，处死，病理切片，检查主要脏器是否正常。
2.618F-Fethypride大鼠主要脏器生物学分布实验
大鼠尾静脉注射18F-Fethypride溶液，分别于注射后10min、30min、60min、90min和120min处死，取适量心、肝、脾、肺、肾等样本，生理盐水冲洗干净，滤纸吸干水分，天平测量样本质量，γ-计数仪测量放射性计数，计算每克组织百分注射剂量率(ID%/g)。
2.718F-Fethypride大鼠脑组织生物学分布实验
大鼠尾静脉注射18F-Fethypride溶液，分别于注射后10min、30min、60min、90min和120min处死，取大脑额叶、顶叶、颞叶、纹状体、海马、丘脑和小脑等样本，生理盐水冲洗干净，滤纸吸干水分，天平测量样本质量，γ-计数仪测量放射性计数，计算每克组织百分注射剂量率(ID%/g)。
2.818F-Fethypride药代动力学实验
大鼠尾静脉注射放射性药物18F-Fethypride溶液，分别于注射后不同时间尾尖部取血50μl，液相色谱-质谱联用仪进行分析测量。
2.9PET/CT扫描
正常大鼠与帕金森氏病大鼠分别尾静脉注射放射性药物18F-Fethypride溶液，10%水合氯醛麻醉、固定，置检查床中心视野进行PET/CT扫描。
3.结果
3.1正电子放射性药物18F-Fethypride质量控制
18F-Fethypride溶液无色、澄清、透明、无杂质，pH值为7，符合规定。TLC法测得的放化纯度为100%，Rf值为0.48；HPLC法测得的放化纯度为99%，保留时间t(R)为3.09min。通过换算，鲎试剂法测得的细菌内毒素含量<5EU/ml，符合规定。追溯性无菌试验结果显示，两种不同培养基在不同的培养温度无菌试验均合格，未有杂菌生长。动物异常毒性实验表明，7天后小鼠和豚鼠均健康存活，体重增加，无异常反应。氨基聚醚(K2.2.2)含量平均值为13.7μg/ml，小于药典规定的25μg/ml，符合标准。质量控制实验说明放射性药物18F-Fethypride是合格且安全的。
3.2脂水分配系数
18F-Fethypride脂水分配系数(Log P)分别为2.4和2.2，说明18F-Fethypride脂溶性大，有利于通过血脑屏障进入脑组织。
3.3稳定性实验
室温放置5h后，TLC法测得放化纯度仍大于95%，有部分脱氟现象，多在4h以后出现，所占比例很小，低于5%。可见，放射性药物18F-Fethypride稳定性很好，适合临床应用。
3.4急性毒性实验
病理切片结果显示：与阴性对照相比，肝脏、肾脏未见异常。小鼠的最大注射剂量相当于人用注射剂量的500倍，表明18F-Fethypride毒性作用较小，应用安全。
3.518F-Fethypride大鼠主要脏器生物学分布实验
18F-Fethypride主要分布在肝脏和肾脏，随时间延长而逐渐减少，心脏的摄取一直很低。肾脏、脾脏、肺部的药物清除速率较快，肝脏的清除速率较慢，说明18F-Fethypride通过肝脏代谢，肾脏排泄，与苯甲酰胺类化合物的代谢和排泄途径相符。
3.618F-Fethypride大鼠脑组织生物学分布实验
在脑组织中18F-Fethypride主要分布在纹状体，丘脑、大脑的额叶、顶叶、颞叶和小脑分布很低。药物的清除速率小脑最快，纹状体最慢。随着时间的延长，纹状体/小脑(靶/非靶)摄取比值逐渐增加，说明18F-Fethypride能与纹状体中的多巴胺受体特异性结合，且亲和力高。
3.718F-Fethypride药代动力学实验
用DAS3.0药代动力学软件对血药浓度进行房室模型拟合，根据AIC最小，R2最大原则，放射性药物18F-Fethypride在大鼠体内的动力学过程符合二室模型。18F-Fethypride在大鼠体内表观分布容积大，说明其脂溶性大，有利于通过血脑屏障进入脑组织。18F-Fethypride在大鼠体内的半衰期小于体外半衰期，提示其在体内消除较快，降低了毒副作用，这与急性毒性实验结果相一致。
3.8PET/CT扫描
PET/CT扫描显示：18F-Fethypride快速进入大鼠各个主要脏器，并快速清除；肝脏为主要代谢器官，肾脏为主要排泄器官；可通过血脑屏障迅速进入脑组织，在纹状体有特异性摄取，清除速率较慢，与脑组织和主要脏器的生物学分布实验结果基本一致。帕金森氏病大鼠纹状体对18F-Fethypride的摄取明显高于正常大鼠，但右侧纹状体(毁损侧)与左侧(健侧)相比，没有显著变化，可能由于本实验使用的是临床型PET/CT扫描仪，主要用于人体扫描，相对于体积较小的大鼠，空间分辨率低、容积效应差。
4.结论
4.1以香草酸甲酯为原料，经7步常规反应，对每步产物进行核磁共振和高分辨质谱表征分析，成功合成18F-Fethypride前体化合物(s)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲酰基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯。
4.2通过亲核取代反应，放射性18Fˉ成功标记，合成正电子放射性药物18F-Fethypride，质量控制实验表明其安全、合格。
4.318F-Fethypride脂水分配系数适宜，能快速通过血脑屏障，该放射性药物稳定、对动物毒性作用小，适合临床静脉注射。
4.418F-Fethypride主要通过肝脏代谢，肾脏排泄，能与纹状体中多巴胺受体特异性结合，亲和力高。
4.5用DAS3.0药代动力学软件对血药浓度进行房室模型拟合，根据AIC最小，R2最大原则，正电子放射性药物18F-Fethypride在大鼠体内的动力学过程符合二室模型。
4.6帕金森氏病大鼠纹状体对放射性药物18F-Fethypride的摄取明显高于正常大鼠，可能是多巴胺受体水平上调所致。
本课题完成了正电子放射性药物18F-Fethypride的前体设计、化学合成、放射性标记、质量控制实验、生物学分布实验、药代动力学实验以及PET/CT扫描等一系列临床前实验工作，为其应用于临床帕金森氏病的诊断奠定了实验基础。
PET/CT is currently one of the most widely used clinical molecular imagingdetection technique which can realize the advance of medical imaging function fromreflecting human body structure change to the metabolic changes. For its sensitivity,accuracy, specificity and precise positioning, this technique can be used to monitor thedistribution and variation of radioactive drugs labeled by positron nuclide in the bodyquantitatively, dynamically and non-invasively, reflect the physiological and bio-chemical changes in vivo at the molecular level, provide us with an ideal platform fordrug screening. The choice of positron radiopharmaceuticals is of great importance forPET/CT imaging scanning.
Parkinson’s Disease, one of the three common kinds of nervous systemdegenerative diseases, is a kind of chronic, insidious disease among the elder people.Parkinson’s Disease has high heterogeneity. Patients will undergo different diseaseprogression. Without any specific diagnostic methods existing, the diagnosis mainlyrely on the medical history, clinical symptom and physical sign. It is more difficult todiagnose when patients only have some atypical clinical symptoms, especially whenpatients are asymptomatic (subclinical type). Most patients’ symptoms can be wellcontrolled through medical treatment at early stage. Patients’ condition will be out ofcontrol due to the patients’ poor response to drugs at middle and advance stage. Thesymptom of stiffness will appear and the patients would not be able to look afterthemselves, and their life quality will severely deteriorated. Therefore early diagnosisand treatment are particularly important.
With the rapid development of molecular nuclear medicine and new positrondrugs, a lot of specific positron radioactive imaging agents have been developed,aimed directly at Parkinson’s Disease. Through PET/CT scanning, abnormal changescan be found in time from metabolism and function imaging before the anatomicalstructure change happens so that the goal of early diagnosis and timely treatment can be achieved.
1. Objective
The main objective of this work is to develop a new type of18F-FethypridePET/CT imaging agent for the early diagnosis of Parkinson’s Disease. Each product inthe process of the precursor synthesis will undergo nuclear magnetic resonance (NMR)and high resolution mass spectrometry analysis in order to determine whether theproducts are target products. Grope for the radioactive method by18Fˉlabeling, theoptimum reaction conditions and a series of quality control tests of the final products.Investigate the clinical application feasibility of radioactive imaging agent18F-Fethypride through pre-clinical acute toxicity test, stability test, biodistribution testand pharmacokinetic test.
2. Methods
2.1A new type of PET/CT imaging agent with vanillic acid methyl ester as rawmaterial was prepared, involving7-step conventional reactions and1step radioactive18Fˉlabeling. This new agent will have great potential application prospect was for thesimple synthesis method and the cheap and widely available raw material. What’smore, the substituent on nitrogen can be further optimized.
2.2Positron Radiopharmaceutical18F-Fethypride Quality Control
2.2.1Clarity Detection
Detect the clarity by turbidimetric method. It was clear and qualified when theturbidity is below0.5turbidity standard solution.
2.2.2pH Detection
Determine pH value of the solution by using pH test strips.
2.2.3Radiochemical Purity Detection
Detect the radiochemical purity of18F-Fethypride solution by HPLC method andTLC method.
2.2.4Bacterial Endotoxin Detection
Measure the bacterial endotoxin of18F-Fethypride solution by TachypleusAmebocyte Lysate(TAL) reagent method. It was qualified when the content ofbacterial endotoxin was below10EU/ml.
2.2.5Sterility Test
18F-Fethypride solution was vaccinated in two different medium respectively andplaced at different temperatures to cultivate for14days. It was qualified if no bacterialgrew in the medium tube.
2.2.6Abnormal Toxicity Test
Lab animals, including mice and guinea pigs, were intraperitoneally injected withdifferent doses of radiopharmaceutical18F-Fethypride and were observed for sevendays. During the period of observation, the test was qualified if the animals were ingood health, without abnormal reactions observed and gaining in weight.
2.2.7K2.2.2Content Detection
Detect the K2.2.2content of18F-Fethypride by Spectrophotometric method. Itwas qualified if the figure was not above25mg/ml.
2.3Lipo-hydro Partition Coefficient
Determine the radiocounting of Radiopharmaceutical18F-Fethypride with γ-radioactive counter when it was in n-butyl alcohol phase and water phase. The lipo-hydro partition coefficient(Log P) was the logarithm of both radiocountings ratios.
2.4The Stability Test
To detect, analyze and evaluate its stability,18F-Fethypride solution was placed atroom temperature and in static state for60min,90min,120min,180min,240min,300min respectively after radioactive labeling. It was proved to be stable if theradioactive chemical purity(RCP) was not less than90%.
2.5Acute Toxic Test
Kunming mice were injected with different doses of radiopharmaceutical18F-Fethypride into the tail vein. After7-day’s observation, they were killed andpathological section was done to check whether the main organs were normal.
2.618F-Fethypride Biodistribution Test in the Main Organs in Rat
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein and were killed10min,30min,60min,90min and120min respectively afterinjection. Adequate amount of samples from heart, liver, spleen, lung and kidney wererinsed in saline, blotted up moisture with filter paper. Weigh the samples with thebalance and determine the radiocounting with γ-radioactive counter. Hereby thepercentage of injected dose per gram (ID%/g) was calculated.
2.718F-Fethypride Biodistribution Test of Brain Tissue in Rat
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein, were killed10min,30min,60min90min and120min respectively after injection.Adequate amount samples from frontal lobe, parietal lobe, temporal lobe, striatum,hippocampus, hypothalamus and cerebellum were taken and rinsed in saline, blotted upmoisture with filter paper. Weigh the samples with balance and determine theradiocounting with γ-radioactive counter. Hereby the percentage of injected dose pergram (ID%/g) was calculated.
2.818F-Fethypride Pharmacokinetic Test
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein.50ml blood sample was taken at different time and was analyzed by using liquidchromatography-mass spectrometry(LC-MS).
2.9PET/CT Scan
Normal rats and PD rats were injected with radiopharmaceutical18F-Fethypridesolution into the tail vein and were fixed in center field of examination bed afteranesthesia with10%chloral hydrate, supine position for PET/CT scanning.
3. Results
3.1Positron Radiopharmaceutical18F-Fethypride Quality Control
18F-Fethypride solution was colorless, clear, transparent, without impurities andwith pH value of7, comforming to the rules. RCP was100%by TLC method, the Rfvalue was0.48; RCP was99%by HPLC method, t(R) was3.09min. The content ofbacterial endotoxin was below5EU/ml by Tachypleus Amebocyte Lysate reagentmethod through the conversion, conforming to the rules. Traceability sterility testresult showed that18F-Fethypride solution was qualified and no bacterial grew in twodifferent medium at different culture temperature. Animal abnormal toxicity testshowed that mice and guinea pigs were alive after7-day’s experiment. The animalshad increase in weight and no abnormal reactions were observed. The averageKryptofix2.2.2(K2.2.2) content was13.7mg/ml, less than25mg/ml in Pharmacopoeia,conforming to the standard. Quality control tests indicated that positron radio-pharmaceutical18F-Fethypride was qualified and safe.
3.2Lipo-hydro Partition Coefficient
LogP of radiopharmaceutical18F-Fethypride were2.4and2.2, which indicatedthat18F-Fethypride had good fat-solubility which helped radiopharmaceutical 18F-Fethypride to pass through the blood-brain barrier into the brain tissue.
3.3The Stability Test
Radioactive chemical purity(RCP) still exceeded95%by TLC method5hoursafter keeping at room temperature. There were some defluorization phenomenon4hours later, but the percentage was very small, less than5%. So the stability ofradiopharmaceutical18F-Fethypride was good, and suitable for clinical application.
3.4Acute Toxic Test
Compared with negative control group, no abnormal phenomenon were observedin livers and kidneys through pathological section. The maximum injection doses formice was as many as500times of that for the human being, which indicated thatradiopharmaceutical18F-Fethypride had less toxic effects and was safe in use.
3.518F-Fethypride Biodistribution Test of Main Organs in Rats
Radiopharmaceutical18F-Fethypride was mainly distributed in the liver andkidney and radioactivity gradually decreased with the passage of time. The intake ofheart was in a lower level. Clearance rates in kidney, spleen and lung were faster, butslower in hepatic. It indicated that18F-Fethypride was metabolized through the liver,and excreted through the kidney, which was coincided with benzamide compounds.
3.618F-Fethypride Biodistribution Test of Brain Tissue in Rats
Radiopharmaceutical18F-Fethypride was mainly distributed in the thalamus, thefrontal lobe and parietal lobe, temporal lobe and the least in cerebellum. Clearance ratein the cerebellum was the fastest, with the slowest clearance rate in the striatum.Striatum/Cerebellum gradually increased with the extension of time, which indicatedthat18F-Fethypride had specific and high affiliative bind with the dopamine D2receptor in the striatum.
3.718F-Fethypride Pharmacokinetic Test
The half-life of18F-Fethypride in vivo was47.62min, less than the half-life of109.8min in vitro, it illustrated18F-Fethypride eliminated quickly in vivo afterintravenous drug, reduced the side effects, which was consistent with the results ofacute toxicity experiment.Hepatic extraction yield (ER=CL/Q) of18F-Fethypride inrats was3.36, it showed that the liver intake of radiopharmaceutical18F-Fethypridewas larger, which was consistent with the results of biodistribution test in vivo in rats.
3.8PET/CT Scan
PET/CT scan showed that radiopharmaceutical18F-Fethypride rapidly entered into all the major organs of rats and quickly cleared. The liver was the major metabolicorgan, and the kidney was the major excretory organ. Radiopharmaceutical18F-Fethypride could quickly pass through the blood brain barrier into the brain tissueand specific uptake was observed in the striatum. Clearance rate was low. It iscoincided with the results of biodistribution test in the brain tissue and major organs invitro. The right side of the striatum (damaged) of Parkinson's rats obviously took inmore18F-Fethypride than normal rats, but no obvious differences were observed in theleft side (healthy side). That may be because the clinical type PET/CT was mainly usedfor human being, not for small animals. It had lower spatial resolution and poorvolume effect for those relatively small animals.
4. Conclusions
4.1A new precursor compound of18F-Fethypride with vanillic acid methyl ester as araw material was successfully synthetized after7-step conventional reaction. Productsat different stages all undergo nuclear magnetic resonance (NMR) and high resolutionmass spectrometry analysis. The precursor compound was (s)-3-[5-{(1-ethylpyrrolidin-2-yl) methylcarbamoyly}-2,3-dimethoxy phenyl] propyl-4-methyl benzemide.
4.2Positron radiopharmaceutical18F-Fethypride was successfully labelled throughnucleophilic substitution reaction. Quality control tests indicated it was qualified andsafe.
4.3Lipo-hydro partition coefficient of radiopharmaceutical18F-Fethypride wasappropriate.It could quickly pass through the blood brain barrier and specifically bindwith the corresponding receptor. It was stable, and had low toxic effect. So it issuitable for clinical intravenous injection.
4.4Radiopharmaceutical18F-Fethypride was metabolized through the liver, andexcreted through the kidney. It had specific and high affiliative bind with the dopamineD2receptor in the striatum.
4.5The kinetic courses of18F-Fethypride in rats were described by an open twoartment model with pharmacokinetic software DAS3.0, according to the principle ofthe minimum AIC and the maximum R2.
4.6The right side of the striatum (damaged) of Parkinson's rats obviously took inmore18F-Fethypride than the normal rats. The reason was that dopamine receptorlevels increased in the damaged side.
This research involved a series of pre-clinical experimental tests forradiopharmaceutical18F-Fethypride, including precursor design, chemical synthesis,radioactive labeling, quality control, biodistribution test, pharmacokinetic test andPET/CT scan, etc. It laid an experimental foundation for the application ofradiopharmaceutical18F-Fethypride in clinical diagnosis of Parkinson’s Disease.
帕金森氏病是三大常见的神经系统变性疾病之一，是一种慢性、隐袭性疾病，多见于老年人。帕金森氏病具有高度异质性，没有特异的诊断方法，主要依靠病史、临床症状和体征进行诊断，部分临床症状不典型或无症状的患者诊断更加困难。早期患者通过药物治疗大多可很好地控制症状，至疾病中、晚期由于对药物反应差，症状得不到控制，可出现全身僵硬，生活不能自理，严重影响生活质量，因此早诊断、早治疗显得尤为重要。
随着分子核医学迅速发展和新的正电子药物不断开发，针对帕金森氏病已经研发出多种特异的正电子放射性显像剂，通过PET/CT扫描，可以在解剖结构发生改变之前，从代谢和功能显像方面及时发现异常变化，从而达到早期诊断、及时治疗的目的。
1.目的
自行设计、研发一种新型的PET/CT显像剂18F-Fethypride，用于诊断帕金森氏病。对前体化合物合成中的每种产物进行核磁共振和高分辨质谱表征分析，以确定合成的是目标产物；探索放射性18Fˉ标记方法及最适反应条件，并对终产物进行一系列质量控制；对正电子放射性显像剂18F-Fethypride进行临床前急性毒性实验、稳定性实验、生物学分布实验和药代动力学实验，探讨18F-Fethypride临床应用的可行性。
2.方法
2.1以香草酸甲酯为原料，经7步常规反应和1步放射性18Fˉ标记合成一种新型的具有潜在应用前景的PET/CT显像剂18F-Fethypride，该化合物具有合成方法简单，原料价廉、易得，而且氮上的取代基还可以做进一步优化等优点。
2.2正电子放射性药物18F-Fethypride质量控制
2.2.1澄清度检测：通过比浊法检测18F-Fethypride溶液的澄清度，不超过0.5号浊度标准液的浊度为澄清，即合格。
2.2.2pH值检测：pH试纸检测18F-Fethypride溶液的pH值。
2.2.3放射化学纯度检测：用高效液相色谱法(HPLC)和薄层色谱法(TLC)检测18F-Fethypride溶液的放射化学纯度。
2.2.4细菌内毒素检测：用鲎试剂法检测18F-Fethypride溶液的细菌内毒素，细菌内毒素含量<10EU/ml，判定合格。
2.2.5无菌实验：18F-Fethypride溶液分别接种于2种不同培养基，放置不同温度培养14天后，各管培养基均无杂菌生长，判定合格。
2.2.6异常毒性实验：包括小鼠实验和豚鼠实验，将不同剂量的放射性药物18F-Fethypride腹腔注射受试动物，观察7天，观察期间动物应全部健存，无异常反应，到期后每只体重应增加，则供试品判定合格。
2.2.7氨基聚醚(K2.2.2)含量测定：分光光度法测定18F-Fethypride溶液中K2.2.2的含量，K2.2.2含量不得超过25μg/ml，判定合格。
2.3脂水分配系数测定
用γ-计数器分别测定放射性药物18F-Fethypride在正丁醇相和水相的放射性计数，两者计数比值的对数为脂水分配系数(Log P)。
2.4稳定性实验将18F-Fethypride溶液室温静置，分别于放射性标记后60min、90min、120min、180min、240min、300min测定放射性化学纯度并进行分析，评价18F-Fethypride溶液的稳定性，放化纯度应不低于90%。
2.5急性毒性实验
小鼠尾静脉注射不同浓度的18F-Fethypride溶液，观察7天，处死，病理切片，检查主要脏器是否正常。
2.618F-Fethypride大鼠主要脏器生物学分布实验
大鼠尾静脉注射18F-Fethypride溶液，分别于注射后10min、30min、60min、90min和120min处死，取适量心、肝、脾、肺、肾等样本，生理盐水冲洗干净，滤纸吸干水分，天平测量样本质量，γ-计数仪测量放射性计数，计算每克组织百分注射剂量率(ID%/g)。
2.718F-Fethypride大鼠脑组织生物学分布实验
大鼠尾静脉注射18F-Fethypride溶液，分别于注射后10min、30min、60min、90min和120min处死，取大脑额叶、顶叶、颞叶、纹状体、海马、丘脑和小脑等样本，生理盐水冲洗干净，滤纸吸干水分，天平测量样本质量，γ-计数仪测量放射性计数，计算每克组织百分注射剂量率(ID%/g)。
2.818F-Fethypride药代动力学实验
大鼠尾静脉注射放射性药物18F-Fethypride溶液，分别于注射后不同时间尾尖部取血50μl，液相色谱-质谱联用仪进行分析测量。
2.9PET/CT扫描
正常大鼠与帕金森氏病大鼠分别尾静脉注射放射性药物18F-Fethypride溶液，10%水合氯醛麻醉、固定，置检查床中心视野进行PET/CT扫描。
3.结果
3.1正电子放射性药物18F-Fethypride质量控制
18F-Fethypride溶液无色、澄清、透明、无杂质，pH值为7，符合规定。TLC法测得的放化纯度为100%，Rf值为0.48；HPLC法测得的放化纯度为99%，保留时间t(R)为3.09min。通过换算，鲎试剂法测得的细菌内毒素含量<5EU/ml，符合规定。追溯性无菌试验结果显示，两种不同培养基在不同的培养温度无菌试验均合格，未有杂菌生长。动物异常毒性实验表明，7天后小鼠和豚鼠均健康存活，体重增加，无异常反应。氨基聚醚(K2.2.2)含量平均值为13.7μg/ml，小于药典规定的25μg/ml，符合标准。质量控制实验说明放射性药物18F-Fethypride是合格且安全的。
3.2脂水分配系数
18F-Fethypride脂水分配系数(Log P)分别为2.4和2.2，说明18F-Fethypride脂溶性大，有利于通过血脑屏障进入脑组织。
3.3稳定性实验
室温放置5h后，TLC法测得放化纯度仍大于95%，有部分脱氟现象，多在4h以后出现，所占比例很小，低于5%。可见，放射性药物18F-Fethypride稳定性很好，适合临床应用。
3.4急性毒性实验
病理切片结果显示：与阴性对照相比，肝脏、肾脏未见异常。小鼠的最大注射剂量相当于人用注射剂量的500倍，表明18F-Fethypride毒性作用较小，应用安全。
3.518F-Fethypride大鼠主要脏器生物学分布实验
18F-Fethypride主要分布在肝脏和肾脏，随时间延长而逐渐减少，心脏的摄取一直很低。肾脏、脾脏、肺部的药物清除速率较快，肝脏的清除速率较慢，说明18F-Fethypride通过肝脏代谢，肾脏排泄，与苯甲酰胺类化合物的代谢和排泄途径相符。
3.618F-Fethypride大鼠脑组织生物学分布实验
在脑组织中18F-Fethypride主要分布在纹状体，丘脑、大脑的额叶、顶叶、颞叶和小脑分布很低。药物的清除速率小脑最快，纹状体最慢。随着时间的延长，纹状体/小脑(靶/非靶)摄取比值逐渐增加，说明18F-Fethypride能与纹状体中的多巴胺受体特异性结合，且亲和力高。
3.718F-Fethypride药代动力学实验
用DAS3.0药代动力学软件对血药浓度进行房室模型拟合，根据AIC最小，R2最大原则，放射性药物18F-Fethypride在大鼠体内的动力学过程符合二室模型。18F-Fethypride在大鼠体内表观分布容积大，说明其脂溶性大，有利于通过血脑屏障进入脑组织。18F-Fethypride在大鼠体内的半衰期小于体外半衰期，提示其在体内消除较快，降低了毒副作用，这与急性毒性实验结果相一致。
3.8PET/CT扫描
PET/CT扫描显示：18F-Fethypride快速进入大鼠各个主要脏器，并快速清除；肝脏为主要代谢器官，肾脏为主要排泄器官；可通过血脑屏障迅速进入脑组织，在纹状体有特异性摄取，清除速率较慢，与脑组织和主要脏器的生物学分布实验结果基本一致。帕金森氏病大鼠纹状体对18F-Fethypride的摄取明显高于正常大鼠，但右侧纹状体(毁损侧)与左侧(健侧)相比，没有显著变化，可能由于本实验使用的是临床型PET/CT扫描仪，主要用于人体扫描，相对于体积较小的大鼠，空间分辨率低、容积效应差。
4.结论
4.1以香草酸甲酯为原料，经7步常规反应，对每步产物进行核磁共振和高分辨质谱表征分析，成功合成18F-Fethypride前体化合物(s)-3-[5-{(1-乙基-2-吡咯烷基)甲基胺甲酰基}-2,3-二甲氧基苯基]丙基-4-甲基苯磺酸酯。
4.2通过亲核取代反应，放射性18Fˉ成功标记，合成正电子放射性药物18F-Fethypride，质量控制实验表明其安全、合格。
4.318F-Fethypride脂水分配系数适宜，能快速通过血脑屏障，该放射性药物稳定、对动物毒性作用小，适合临床静脉注射。
4.418F-Fethypride主要通过肝脏代谢，肾脏排泄，能与纹状体中多巴胺受体特异性结合，亲和力高。
4.5用DAS3.0药代动力学软件对血药浓度进行房室模型拟合，根据AIC最小，R2最大原则，正电子放射性药物18F-Fethypride在大鼠体内的动力学过程符合二室模型。
4.6帕金森氏病大鼠纹状体对放射性药物18F-Fethypride的摄取明显高于正常大鼠，可能是多巴胺受体水平上调所致。
本课题完成了正电子放射性药物18F-Fethypride的前体设计、化学合成、放射性标记、质量控制实验、生物学分布实验、药代动力学实验以及PET/CT扫描等一系列临床前实验工作，为其应用于临床帕金森氏病的诊断奠定了实验基础。
PET/CT is currently one of the most widely used clinical molecular imagingdetection technique which can realize the advance of medical imaging function fromreflecting human body structure change to the metabolic changes. For its sensitivity,accuracy, specificity and precise positioning, this technique can be used to monitor thedistribution and variation of radioactive drugs labeled by positron nuclide in the bodyquantitatively, dynamically and non-invasively, reflect the physiological and bio-chemical changes in vivo at the molecular level, provide us with an ideal platform fordrug screening. The choice of positron radiopharmaceuticals is of great importance forPET/CT imaging scanning.
Parkinson’s Disease, one of the three common kinds of nervous systemdegenerative diseases, is a kind of chronic, insidious disease among the elder people.Parkinson’s Disease has high heterogeneity. Patients will undergo different diseaseprogression. Without any specific diagnostic methods existing, the diagnosis mainlyrely on the medical history, clinical symptom and physical sign. It is more difficult todiagnose when patients only have some atypical clinical symptoms, especially whenpatients are asymptomatic (subclinical type). Most patients’ symptoms can be wellcontrolled through medical treatment at early stage. Patients’ condition will be out ofcontrol due to the patients’ poor response to drugs at middle and advance stage. Thesymptom of stiffness will appear and the patients would not be able to look afterthemselves, and their life quality will severely deteriorated. Therefore early diagnosisand treatment are particularly important.
With the rapid development of molecular nuclear medicine and new positrondrugs, a lot of specific positron radioactive imaging agents have been developed,aimed directly at Parkinson’s Disease. Through PET/CT scanning, abnormal changescan be found in time from metabolism and function imaging before the anatomicalstructure change happens so that the goal of early diagnosis and timely treatment can be achieved.
1. Objective
The main objective of this work is to develop a new type of18F-FethypridePET/CT imaging agent for the early diagnosis of Parkinson’s Disease. Each product inthe process of the precursor synthesis will undergo nuclear magnetic resonance (NMR)and high resolution mass spectrometry analysis in order to determine whether theproducts are target products. Grope for the radioactive method by18Fˉlabeling, theoptimum reaction conditions and a series of quality control tests of the final products.Investigate the clinical application feasibility of radioactive imaging agent18F-Fethypride through pre-clinical acute toxicity test, stability test, biodistribution testand pharmacokinetic test.
2. Methods
2.1A new type of PET/CT imaging agent with vanillic acid methyl ester as rawmaterial was prepared, involving7-step conventional reactions and1step radioactive18Fˉlabeling. This new agent will have great potential application prospect was for thesimple synthesis method and the cheap and widely available raw material. What’smore, the substituent on nitrogen can be further optimized.
2.2Positron Radiopharmaceutical18F-Fethypride Quality Control
2.2.1Clarity Detection
Detect the clarity by turbidimetric method. It was clear and qualified when theturbidity is below0.5turbidity standard solution.
2.2.2pH Detection
Determine pH value of the solution by using pH test strips.
2.2.3Radiochemical Purity Detection
Detect the radiochemical purity of18F-Fethypride solution by HPLC method andTLC method.
2.2.4Bacterial Endotoxin Detection
Measure the bacterial endotoxin of18F-Fethypride solution by TachypleusAmebocyte Lysate(TAL) reagent method. It was qualified when the content ofbacterial endotoxin was below10EU/ml.
2.2.5Sterility Test
18F-Fethypride solution was vaccinated in two different medium respectively andplaced at different temperatures to cultivate for14days. It was qualified if no bacterialgrew in the medium tube.
2.2.6Abnormal Toxicity Test
Lab animals, including mice and guinea pigs, were intraperitoneally injected withdifferent doses of radiopharmaceutical18F-Fethypride and were observed for sevendays. During the period of observation, the test was qualified if the animals were ingood health, without abnormal reactions observed and gaining in weight.
2.2.7K2.2.2Content Detection
Detect the K2.2.2content of18F-Fethypride by Spectrophotometric method. Itwas qualified if the figure was not above25mg/ml.
2.3Lipo-hydro Partition Coefficient
Determine the radiocounting of Radiopharmaceutical18F-Fethypride with γ-radioactive counter when it was in n-butyl alcohol phase and water phase. The lipo-hydro partition coefficient(Log P) was the logarithm of both radiocountings ratios.
2.4The Stability Test
To detect, analyze and evaluate its stability,18F-Fethypride solution was placed atroom temperature and in static state for60min,90min,120min,180min,240min,300min respectively after radioactive labeling. It was proved to be stable if theradioactive chemical purity(RCP) was not less than90%.
2.5Acute Toxic Test
Kunming mice were injected with different doses of radiopharmaceutical18F-Fethypride into the tail vein. After7-day’s observation, they were killed andpathological section was done to check whether the main organs were normal.
2.618F-Fethypride Biodistribution Test in the Main Organs in Rat
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein and were killed10min,30min,60min,90min and120min respectively afterinjection. Adequate amount of samples from heart, liver, spleen, lung and kidney wererinsed in saline, blotted up moisture with filter paper. Weigh the samples with thebalance and determine the radiocounting with γ-radioactive counter. Hereby thepercentage of injected dose per gram (ID%/g) was calculated.
2.718F-Fethypride Biodistribution Test of Brain Tissue in Rat
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein, were killed10min,30min,60min90min and120min respectively after injection.Adequate amount samples from frontal lobe, parietal lobe, temporal lobe, striatum,hippocampus, hypothalamus and cerebellum were taken and rinsed in saline, blotted upmoisture with filter paper. Weigh the samples with balance and determine theradiocounting with γ-radioactive counter. Hereby the percentage of injected dose pergram (ID%/g) was calculated.
2.818F-Fethypride Pharmacokinetic Test
Rats were injected with radiopharmaceutical18F-Fethypride solution into the tailvein.50ml blood sample was taken at different time and was analyzed by using liquidchromatography-mass spectrometry(LC-MS).
2.9PET/CT Scan
Normal rats and PD rats were injected with radiopharmaceutical18F-Fethypridesolution into the tail vein and were fixed in center field of examination bed afteranesthesia with10%chloral hydrate, supine position for PET/CT scanning.
3. Results
3.1Positron Radiopharmaceutical18F-Fethypride Quality Control
18F-Fethypride solution was colorless, clear, transparent, without impurities andwith pH value of7, comforming to the rules. RCP was100%by TLC method, the Rfvalue was0.48; RCP was99%by HPLC method, t(R) was3.09min. The content ofbacterial endotoxin was below5EU/ml by Tachypleus Amebocyte Lysate reagentmethod through the conversion, conforming to the rules. Traceability sterility testresult showed that18F-Fethypride solution was qualified and no bacterial grew in twodifferent medium at different culture temperature. Animal abnormal toxicity testshowed that mice and guinea pigs were alive after7-day’s experiment. The animalshad increase in weight and no abnormal reactions were observed. The averageKryptofix2.2.2(K2.2.2) content was13.7mg/ml, less than25mg/ml in Pharmacopoeia,conforming to the standard. Quality control tests indicated that positron radio-pharmaceutical18F-Fethypride was qualified and safe.
3.2Lipo-hydro Partition Coefficient
LogP of radiopharmaceutical18F-Fethypride were2.4and2.2, which indicatedthat18F-Fethypride had good fat-solubility which helped radiopharmaceutical 18F-Fethypride to pass through the blood-brain barrier into the brain tissue.
3.3The Stability Test
Radioactive chemical purity(RCP) still exceeded95%by TLC method5hoursafter keeping at room temperature. There were some defluorization phenomenon4hours later, but the percentage was very small, less than5%. So the stability ofradiopharmaceutical18F-Fethypride was good, and suitable for clinical application.
3.4Acute Toxic Test
Compared with negative control group, no abnormal phenomenon were observedin livers and kidneys through pathological section. The maximum injection doses formice was as many as500times of that for the human being, which indicated thatradiopharmaceutical18F-Fethypride had less toxic effects and was safe in use.
3.518F-Fethypride Biodistribution Test of Main Organs in Rats
Radiopharmaceutical18F-Fethypride was mainly distributed in the liver andkidney and radioactivity gradually decreased with the passage of time. The intake ofheart was in a lower level. Clearance rates in kidney, spleen and lung were faster, butslower in hepatic. It indicated that18F-Fethypride was metabolized through the liver,and excreted through the kidney, which was coincided with benzamide compounds.
3.618F-Fethypride Biodistribution Test of Brain Tissue in Rats
Radiopharmaceutical18F-Fethypride was mainly distributed in the thalamus, thefrontal lobe and parietal lobe, temporal lobe and the least in cerebellum. Clearance ratein the cerebellum was the fastest, with the slowest clearance rate in the striatum.Striatum/Cerebellum gradually increased with the extension of time, which indicatedthat18F-Fethypride had specific and high affiliative bind with the dopamine D2receptor in the striatum.
3.718F-Fethypride Pharmacokinetic Test
The half-life of18F-Fethypride in vivo was47.62min, less than the half-life of109.8min in vitro, it illustrated18F-Fethypride eliminated quickly in vivo afterintravenous drug, reduced the side effects, which was consistent with the results ofacute toxicity experiment.Hepatic extraction yield (ER=CL/Q) of18F-Fethypride inrats was3.36, it showed that the liver intake of radiopharmaceutical18F-Fethypridewas larger, which was consistent with the results of biodistribution test in vivo in rats.
3.8PET/CT Scan
PET/CT scan showed that radiopharmaceutical18F-Fethypride rapidly entered into all the major organs of rats and quickly cleared. The liver was the major metabolicorgan, and the kidney was the major excretory organ. Radiopharmaceutical18F-Fethypride could quickly pass through the blood brain barrier into the brain tissueand specific uptake was observed in the striatum. Clearance rate was low. It iscoincided with the results of biodistribution test in the brain tissue and major organs invitro. The right side of the striatum (damaged) of Parkinson's rats obviously took inmore18F-Fethypride than normal rats, but no obvious differences were observed in theleft side (healthy side). That may be because the clinical type PET/CT was mainly usedfor human being, not for small animals. It had lower spatial resolution and poorvolume effect for those relatively small animals.
4. Conclusions
4.1A new precursor compound of18F-Fethypride with vanillic acid methyl ester as araw material was successfully synthetized after7-step conventional reaction. Productsat different stages all undergo nuclear magnetic resonance (NMR) and high resolutionmass spectrometry analysis. The precursor compound was (s)-3-[5-{(1-ethylpyrrolidin-2-yl) methylcarbamoyly}-2,3-dimethoxy phenyl] propyl-4-methyl benzemide.
4.2Positron radiopharmaceutical18F-Fethypride was successfully labelled throughnucleophilic substitution reaction. Quality control tests indicated it was qualified andsafe.
4.3Lipo-hydro partition coefficient of radiopharmaceutical18F-Fethypride wasappropriate.It could quickly pass through the blood brain barrier and specifically bindwith the corresponding receptor. It was stable, and had low toxic effect. So it issuitable for clinical intravenous injection.
4.4Radiopharmaceutical18F-Fethypride was metabolized through the liver, andexcreted through the kidney. It had specific and high affiliative bind with the dopamineD2receptor in the striatum.
4.5The kinetic courses of18F-Fethypride in rats were described by an open twoartment model with pharmacokinetic software DAS3.0, according to the principle ofthe minimum AIC and the maximum R2.
4.6The right side of the striatum (damaged) of Parkinson's rats obviously took inmore18F-Fethypride than the normal rats. The reason was that dopamine receptorlevels increased in the damaged side.
This research involved a series of pre-clinical experimental tests forradiopharmaceutical18F-Fethypride, including precursor design, chemical synthesis,radioactive labeling, quality control, biodistribution test, pharmacokinetic test andPET/CT scan, etc. It laid an experimental foundation for the application ofradiopharmaceutical18F-Fethypride in clinical diagnosis of Parkinson’s Disease.
引文
[1]张秀文,张永寿,刘乃智. PET-CT工作原理及应用[J].中国医学装备,2012,9(11):22-25
[2]王荣福. PET/CT分子影像新技术应用[M].北京:北京大学医学出版社,2011:750-765
[3] Wahl R L, Beanlands R S. Principle and Practices of PET and PET/CT [M].Philadelphia: Lippincott Williams&Wilkins,2008,15:360-423
[4] Bouchelouche K, Oehr P. Positron Emission Tomography and Positron EmissionTomography/Computerized Tomography of Urological Malignancies: An Updateeview[J]. The Journal of Urology,2008,179(1):34-45
[5] Rajendran J G,Mankoff D A. Beyond Detection: Novel Applications for PETImaging to Guide Cancer Therapy[J]. J Nucl Med,2007,48(6):855-866
[6]王强,王荣福.当代最先进分子影像新技术--PET/MRI[J].中国医疗器械信息,2011,17(4):4-7
[7] Israel O, Kuten A. Early detection of cancer recurrence:18F-FDG PET/CT canmake a difference in diagnosis and patient care[J]. J Nucl Med,2007,48(1):28-35
[8] Buck A K, Herrmann K, Stargardt T, et al. Economic evaluation of PET andPET/CT in oncology: evidence and methodologic approaches[J]. J Nucl Med,2010,51(3):401-412.
[9] Maecke H R, Andre J P.68Ga-PET radiopharmacy:A generator-based alternativeto18F-radiopharmacy[J]. Ernst Schering Res Found Workshop,2007,62(5):215-242
[10]张宝石,周乃康,张锦明,于长海. PET示踪剂的临床应用及研究进展[J].中国医药导刊,2011,13(2):234-237
[11] Lu X,Wang R F. A concise review of current radiopharmaceuticals in tumorangiogenesis imaging[J]. Curr Pharm Des,2012,18(8):1032-1040
[12]贾峰涛,杨星,洪军,张林.医用回旋加速器原理及应用[J].医疗设备信息,2006,21(6):37-38
[13]梁银杏,叶桦.关于我国正电子放射性药品新药注册管理的建议[J].中国新药与临床杂志,2012,31(2):68-71
[14]陈开宇,李新平,陈盛新.正电子放射性药物的应用现状与进展[J].药学实践杂志,2012,30(3):175-177
[15]张锦明,田嘉禾.国内正电于放射性药物发展现状简介[J].同位素,2006,19(4):240-243
[16] Direcks W G, Berndsen S C, Proost N, et al.[18F]FDG and [18F]FLT uptake inhuman breast cancer cells in relation to the effects of chemotherapy: an in vitrostudy[J]. Br J Cancer,2008,99(3):481-487
[17]罗家伦,徐慧琴.11C标记的放射性药物在PET/CT中的应用[J].安徽医学,2009,30(7):728-731
[18]杨敏,潘栋辉,徐宇平,王颂佩.苯甲酰胺类多巴胺D2受体显像剂18F-Fallypride的制备和生物分布[J].核技术,2008,31(5):360-363
[19] Florian A, Timo S S, Sabine H, Ursula S, Bernhard H, Peter R, Cornelius W,Wolfgang A W, Christian W, Philipp T M. Assessment of Striatal DopamineD2/D3Receptor Availability with PET and18F-Desmethoxy-fallypride:Comparison of Imaging Protocols Suited for Clinical Routine[J]. The Journal ofNuclear Medicine,2012,53(10):1558-1564
[20] Jenny C, Elske V, Michel, Tom M, Guy B, Stephan C, Koen V L. Optimized InVivo Detection of Dopamine Release Using18F-Fallypride PET[J]. The Journalof Nuclear Medicine,2012,53(10):1565-1572
[21]孙传金,朱虹,方可元.国产氟多功能模块合成雌激素受体显像剂16α-18F-17β-雌二醇[J].同位素,2012,25(3):156-159
[22] Liu R S, Chou T K, Chang C H, et al. Biodistribution, Phannaeokinetics andPET Imaging of18F-FMISO,18F-FDG and18F-Fac in asareoma andinflammation-bearing mouse model[J]. Nucl Med Biol,2009,36(3):305-312
[23]张锦明,郭喆,田嘉禾,王武尚. β淀粉样蛋白显像剂2-(4-N-11C-甲胺苯基)-6-羟基苯并噻唑的研究[J].中华核医学杂志,2008,28(6):397-399
[24] Divgi C R. Molecular imaging of pulmonary cancer and inflammation[J]. ProcAm Thorac Soc,2009,6(5):464-468
[25] Lee T S, Ahn S H, Moon B S, et al. Comparison of18F-FDG,18F-FET and18F-FLT for differentiation between tumor and inflammation in rats[J]. Nucl82Med Biol,2009,36(6):681-686
[26] Christian F, Gabriele P, Johannes L, Guido B, Christopher U, Paul C, Peter B,Klaus T. The Value of the Dopamine D2/3Receptor Ligand18F-Desmethoxyfallypride for the Differentiation of Idiopathic and Nonidiopathic ParkinsonianSyndromes[J]. The Journal of Nuclear Medicine,2010,51(4):581-587
[27] Kasper B, Egerer G, Gronkowski M, et al. Functional diagnosis of residuallymphomasafter radiochemotherapy with positron emission tomographycomparing FDG-and FLT-PET[J]. Leuk Lymphoma,2007,48(4):746-753
[28]李英华,关锋,代玉银,林承赫.正电子放射性分子显像剂诊断帕金森氏病的研究进展[J]核技术2012,35(3):211-215
[29]李光慧,盛许晶,朱建华.多巴胺受体显像剂125I-DMAIBZM的合成及生物分布实验[J].高等学校化学学报,2010,31(12):2413-2418
[30] Gao M Z, Wang M, Mock B H, Glick B E, Yoder K K, Hutchins G D, Zheng QH. An improved synthesis of dopamine D2/D3receptor radioligands [11C]fallypride and [18F]fallypride[J]. Applied Radiation and Isotopes,2010,68(6):1079-1086
[31]姚志文,丁正同,张政伟,蒋雨平.阿尔茨海默病正电子显像剂11C-6-OH-BTA-1的制备[J].中华核医学杂志,2007,27(6):327-329
[32]周玲,管一晖,薛方平,张政伟,蒋雨平.脑乙酰胆碱酯酶的PET显像剂11C-4-乙酰氧基-N-甲基哌啶在大鼠体内分布的研究[J].中华临床神经科学,2008,16(6):580-584
[33]蒋泉福,吴春英,陆春雄.一种99mTc标记的5-HT1A受体显像剂的合成与标记[J].同位素,2006,19(3):150-153
[34]王明芳,唐刚华,李葆元,王全师,罗志福.11C-PK11195的自动化合成及其生物学分布[J].中华核医学杂志,2008,28(6):400-403
[35]张锦明,桂媛,徐志红,张晓军,向晓辉,田嘉禾.阿片受体显像剂11C-Carfentanil的前体合成及放射性标记[J].核化学与放射化学,2011,33(4):252-256
[36]肖颖,张本恕. UCH-Ll基因多态性与帕金森病的关联研究[J].中华医学遗传学杂志,2008,25(5):586-587
[37]熊慧,张雅坤.帕金森病致病基因DJ-1的研究[J].内科理论与实践,2010,5(5):390-392
[38]杜青青,杨学超,吴娟娟. PD相关基因LRRK2表达调控的初探[J].南通大学学报(医学版),2011,31(6):409-413
[39] Nicholas T V, Jeffrey M M, Alexander K C, James E H, Jogesh M, DhanabalanM R, Jerry N, Richard J D, Mary L S, Bradley T C. High-affinity dopamine D2/D3PET radioligands18F-fallypride and11C-FLB457: A comparison of kineticsin extrastriatal regions using a multiple-injection protocol[J]. Journal of CerebralBlood Flow&Metabolism,2010,30(5):994-1007
[40] Adriana G, Mohammad R M, Cristian C, Eveguen S, Norah M, Jonathan L K,George C, Jogeshwar M.18F-Fallypride PET of Pancreatic Islets: In Vitro and InVivo Rodent Studies[J]. The Journal of Nuclear Medicine,2011,52(7):1125-1132
[41]陈贵兵,吴华,彭添兴.正电子显像剂11C-匹兹堡化合物B的化学合成及其临床应用[J].国际放射医学核医学杂志,2008,32(3):158-161
[42] Aumann K M, Hungerford N L, Coster M J. First enantioselective synthesis ofmethyl (+)-7-methoxyanodendroate, an antitubercular dihydrobenzofuran[J].Tetrahedron Letters,2011,52:6988–6990
[43] Wu Zh. Liang Z Y, Li W, Wang Q A. Synthesis of (±)-Demethylnitidanin,Herpetol and Salvinal as well as Their Glycosyl Derivatives[J]. Chem ResChinese Universities,2011,27(6):949-952
[44] Stichelberger M, Desbouis D, Spiwok V, et al. Synthesis, in vitro and in silicoassessment of organometallic Rhenium(I) and Technetium(I) thymidinecomplexes[J].Journal of Organometallic Chemistry,2007,692(6):1255-1264
[45] KoenV L, Kristien C, Eduard D H, Tjibbede G, WimV. Combined StriatalBinding and Cerebral Influx Analysis of Dynamic11C-Raclopride PETImproves Early Differentiation Between Multiple-System Atrophy andParkinson Disease[J]. The Journal of Nuclear Medicine,2010,51(4):588-595
[46] Monte S, Buchsbaum, Br adley T, et al. D2/D3dopamine receptor binding with
[F]-18fallypride in thalamus and cortex of patients with schizophrenia[J].Schizophrenia Research,2006,85:232-244
[47] Axel R, Erik M, Guido B, Stefan F, Sebastian N, Franz J G, Peter B. Validationof the Octamouse for Simultaneous18F-Fallypride Small-Animal PETRecordings from8Mice[J]. The Journal of Nuclear Medicine,2010,51(10):1576-1583
[48]贾晓娟,王雪晴,许泽清,李慧.两种放射性药物标记法在单光子发射计算机断层显像脑血流灌注显像的应用探讨[J].实用医技杂志,2013,20(4):393-394
[49]曾华辉,张华北.国内心、脑、肿瘤放射性诊断药物研究进展[J].化学进展,2011,23(7):1485-1492
[51]张锦明,田嘉禾,姚树林,丁为民,尹大一,刘伯里.11C-Raclopride的快速制备及生物学评价[J].中华核医学杂志,2008,28(4):227-230
[52]杨敏,徐宇平,潘栋辉,王颂佩,罗世能.18F-Fallypride的自动化合成与小动物PET显像[J].中华核医学杂志,2008,28(4):223-227
[53] Ingo V, Lisa P, Mardjan R, Robert L, Oliver W, Frank R, Peter B, Dean F W.The applicability of SRTM in [18F] fallypride PET investigations: impact ofscan durations[J]. Journal of Cerebral Blood Flow&Metabolism,2011,31(9):1958-1966
[54]张锦明,郑昕,郭喆,田嘉禾.全自动合成3-18F-2-羟基丙烷-2-硝基咪唑及临床前研究[J].首都医科大学学报,2008,29(1):8-11
[55]孙伟张,周克,蒋长青,郭正奎.外周苯二氮卓受体示踪剂18F-SAN的合成[J].西南国防医药,2009,19(9):884-886
[56]李谷才,尹端沚,夏姣云,汪勇先.多巴胺D4受体显像剂18F-FDTP的研制和受体结合分析[J].核化学与放射化学,2008,30(3):167-173
[57] Shao X, Kilbourn M R. A Simple Modification of GE Tracerlab FX C Pro forRapid Sequential Preparation of11C-Carfentanil and11C-Raclopride [J]. ApplRadiat Isot,2009,67:602-605
[58] Windhorst A D, Klein P J, Eisenbarth J, et al.3'-Sulfonylesters of2,5'–anhydro-1-(2-deoxy-[beta]-d-threo-pentofuranosyl)thymine as precursors for thesynthesis of [18F]FLT: syntheses and radiofluorination trials[J]. NuclearMedicine and Biology,2008,35(4):413-423
[59] Celen S, de Groot T, Balzarini J, et al. Synthesis and evaluation of a99mTc-MA-propyl-thymidine complex as a potential probe for in vivo visualization oftumor cell proliferation with SPECT[J]. Nuclear Medicine and Biology,2007,34(3):283-291
[60] Desbouis D, Schubiger P A, Schibli R. Synthesis of tricarbonyl rhenium andtechnetium complexes of a5'-carboxamide5-ethyl-2'-deoxyuridine for selectiveinhibition of herpes simplex virus thymidine kinase1[J]. Journal ofOrganometallic Chemistry,2007,692(6):1340-1347
[61]张锦明,田嘉禾.18F-FDG的质量控制及方法[J].中华核医学杂志,2005,25(6):383-384
[62]张晓军,向晓辉,张锦明,田嘉禾.11C-Carfentanil的质量控制[J].同位素,2013,26(1):29-40
[63]澄清度检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅣB71-71
[64]放射性药品检定法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录Ⅷ123-129
[65]邓怀福,陈萍. PET肿瘤显像剂S-11C-甲基-L-半胱氨酸的制备与质量控制[J].中国医疗前沿,2013,8(7):8-11
[66]许飞,杨敏,潘栋辉.18F-Fallypride标记前体的反相HPLC测定[J].实用临床医药杂志,2008,12(4):44-45
[67]郭莘,史道华.18F-16α-17β-氟雌二醇注射液细菌内毒素检查法的建立[J].中国现代应用药学,2013,30(3):322-326
[68]细菌内毒素检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥE99-102
[69]无菌检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥH103-105
[70]异常毒性检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥC98-98
[71] Tiantian M, Huihui J, Wen J Y, Wei F, Cheng P, Feng G, Xian Z, Yan P.Preparation and biodistribution of [18F]FP2OP as myocardial perfusion imagingagent for positron emission tomography[J]. Bioorganic&Medicinal Chemistry,2010,18:1312-1320
[72]张贇,吴战宏,李方,朱立.2-18F-A-85380的制备与Micro PET显像[J].同位素,2008,21(1):15-19
[73]张永学,黄钢,匡安仁,李亚明.《核医学》2010年第二版[M].北京:人民卫生出版社,2010,53-54
[74]王荣福,刘萌.活体核素示踪神经受体研究进展[J].北京大学学报,2007,39(5):550-554
[75]钱明理.分子影像学技术及其新进展[J].中国医疗器械杂志,2012,36(4):277-281
[76] Lu C, Jiang Q, Yu H, et al. Preparation and preliminary biological evaluation of99mTc-ANMdU[J]. Nucl Sci Tech,2010,21(2):106-109
[77]谭海波.正电子发射断层(PET)基础与临床研究:11C-左旋千金藤啶碱制备方法及生物学初步评价[J].辽宁中医杂志,2008(1):58-59
[78] Deng H F, Tang G H, Wang H L, et al. Radiosynthesis and evaluation of11C-CYS as an oncologic PET tracer[J]. J Nucl Med,010,51(l2):366-370
[79]张锦明,郭喆,田嘉禾,王武尚. Aβ斑块显像剂11C-苯并呋喃衍生物的研究[J].中华核医学杂志,2007,27(1):38-40
[80]杨敏.18F-Fallypride:一种多巴胺D2受体PET显像剂[J].国外医学.放射医学核医学分册,2003,27(6):259-262
[81] Teng B, Bai Y, Chang Y, et al. Technetium-99m-labeling and synthesis ofthymidine analogs: Potential candidates for tumor imaging[J]. Bioorganic&Medicinal Chemistry Letters,2007,17(12):3440-3444
[82] Eckel F, Herrmann K, Schmidt S, et al. Imaging of proliferation inhepatocellular carcinoma with the in vivo marker18F-fluorothymidine[J]. J NuclMed,2009,50(9):1441-1447
[83] Lee S J, Oh S J, Chi D Y, et al. Simple and highly efficient synthesis of3'-deoxy-3'-[18F]fluorothymidine using nucleophilic fluorination catalyzed byprotic solvent[J]. Eur J Nucl Med Mol Imaging,2007,34(9):1406-1409
[84] Teng B, Bai Y, Chang Y, et al. Technetium-99m-labeling and synthesis ofthymidine analogs: Potential candidates for tumor imaging[J]. Bioorganic&Medicinal Chemistry Letters,2007,17(12):3440-3444
[85] Kato T, Shinoda J, Nakayama N, et al. Metabolite assessment of gliomasusing1IC-methionine,18F-fluorodeoxyglucose and1IC-choline Positron emissiontomography[J]. AJNR,2008,29(6):1176-1118
[86] Chen Z P, Wang S P, Li X M, Liu C Y, Tang J, Luo S N, Cao G X, Zhang L F,Jin J. A one-step automated high-radiochemical-yield synthesis of18F-FECNTfrom mesylate precursor [C].55thannual meeting of Society of NuclearMedicine. New Orlean, USA. J Nucl Med,2008,49(Supplement1):306P
[87] Chen Z P, Wang S P, Tang J, Li X M, Liu C Y, Xu X J, Cao G X. Simplifiedmethod for determining radiochemical purity of99mTc-TRODAT-1[J]. Journal ofRadioanalytical and Nuclear Chemistry,2008,277(3):591-594
[88] Chen Z P, Wang S P, Li X M, Liu C Y, Tang J, Cao G X, Luo S N, Zhang L F,Jin J. A one-step automated high-radiochemical-yield synthesis of18F-FECNTfrom mesylate precursor[J]. Applied Radiation and Isotopes,2008,26(12):1881-1885
[89]彭程,牟甜甜,赵祚全,马云川,张现忠.18F-标记哒嗪酮类似物的制备及其在小鼠体内的生物分布[J].同位素,2013,26(1):23-28
[90] Chen W, Delaloye S, Silverman D H, et al. Predicting treatment response ofmalignant gliomas to bevacizumab and irinotecan by imaging proliferation with
[18F]fluorothymidine positron emission tomography: a pilot study[J]. J ClinOncol,2007,25(30):4714-4721
[91] SFDA. Good preparation practice of positron radioactive drugs in medicalinstitution [S].2006
[92]杨志,朱华.新型PET核素68Ga标记D-脱氧葡萄糖的合成及生物学评价[J].化学学报,2012,70(9):1066-1072
[93]余大富,杨吉生.11C-PIB PET对阿尔茨海默病的诊断价值[J].中华核医学杂志,2009,29(3):214-216
[94]杨洋,崔孟超,汤睿昆,吴瑞,朱霖,张华北. Re/99Tcm(CO)3+－二苯基二氮烯类化合物Ａβ显像剂的制备以及生物评价[J].同位素,2013,26(2):65-71
[95] Teng B, Wang S, Fu Z, et al. Semiautomatic synthesis of3'-deoxy-3'-[18F]fluoro-thymidine using three precursors[J]. Applied Radiation and Isotopes,2006,64(2):187-193
[96]刘昌孝,刘定远.药物动力学概论[M].北京:中国学术出版社,1984:170-269
[97]赵占中.硝唑尼特在山羊体内的药物代谢动力学及毒理学研究[D].北京:中国农业科学院,2009
[98]曹国宪,周杏琴,颜成龙,张建康,钦晓峰.受体显像剂99mTc-NCAM在小鼠脑组织中的药物代谢动力学研究[J].核技术,2010,33(10):797-800
[99] Van L K, Varrone A, Booij J, et al. European Association of Nuclear Medicineguidelines for brain neurotransmission SPECT/PET using dopamine D2receptorligands[J]. Eur J Nucl Med Mol Imaging,2010,37:434–442
[100] Shi J, Zhao L Y, CopersinoM L,et al. PET imaging of dopamine transporteranddrug craving duringmethadone maintenance treatment and after prolongedabstinence in heroin users[J]. Eur Jpharmacol,2008,579:160-166
[101]陈正平,王颂佩,李晓敏,刘春仪,唐婕.18F-FECNT的生物分布特性及小动物PET显像研究[J].中华核医学杂志,2009,29(3):181-184
[102]邓怀福,文富华,唐刚华，孟悛非.18F-氟代乙酸盐自动化合成及其动物实验研究[J].中山大学学报（医学科学版）,2011,32(1):99-103
[103]王洪震,贾正平,郝彦明,钱荣勋,董启榕,徐又佳.188Re-碘化油-羧甲基壳聚糖-纳米微粒在荷S180肉瘤小鼠体内分布与代谢[J].中国组织工程研究与临床康复,2011,15(51):9603-9607
[104]王新艳,张政伟,蒋雨平,孔艳艳,桂媛,胡名扬,华逢春,管一晖. β淀粉样蛋白PET显像剂11C-DPOD的制备及其在动物体内的分布[J].中国临床神经科学,2013,21(1):12-18
[105] Huang Y R, Shih J M, Chang K W, et al.[123I]-Epidepride neuroimaging ofdopamine D2/D3receptor in chronic MK-801-induced rat schizophrenia model[J]. Nucl Med Biol,2012,39(6):826-832
[106]鲍晓,王明伟,徐俊彦,郑宇佳,蒋津津,章英剑.新型18F-RGD二聚体的正常生物分布及U87MG荷瘤裸鼠小动物PET/CT显像研究[J].中国癌症杂志,2010,23(6):408-412
[107]戈宏焱,陈博,许丹,李有田,李洋.柴胡皂苷A对抑郁模型大鼠脑中单胺类神经递质及其代谢产物含量的影响[J].高等学校化学学报,2008,29(8):1535-1538
[108] Laforest R, Longford D, Siegel S, et al. Performance evaluation of the microPET(R)FOCUS-F120[J]. Ieee Transactions on Nuclear Science,2007,54(1):42-49
[109] Wang H, Cai W, Chen K, et a1. A new PET tracer specific for vascularendothelial growth factor receptor2[J]. Eur J Nucl Med Mol Imaging,2007,34(12):2001-2010
[110] Jacobson O, Zhu L, MaY, et al. Rapid and simple onestep F-18labeling ofpeptides[J]. Bioconjug Chem,2011,22(3):422-428
[111]潘栋辉,杨敏,徐宇平.18F-RGD环肽二聚体的自动化合成及小动物PET显像[J].中华核医学与分子影像杂志,2012,32(2):90-94
[112]贺立娟,王玉来,郭蓉娟. PET在神经精神疾病领域的应用进展[J].中华中医药学刊[J].2012,30(12):2639-2641
[113] Shankar V, Lilja S, Brigitte V. A broad overview of positron emissiontomography radiopharmaceuticals and clinical applications: What is new?[J].Semin Nucl Med,2011,41:246-250
[114]陆春雄,王正武,蒋泉福.18F-FLT的制备及其microPET显像[J].同位素,2008,21(3):145-149
[115] Been L B, Elsinga P H, de Vries J, et al. Positron emission tomography inpatients with breast cancer using18F-3'-deoxy-3'-fluoro-l-thymidine(18F-FLT)--a pilot study[J]. European Journal of Surgical Oncology,2006,32(1):39-43
[116]张妍芬,王晓明,王晓煜,曹礼,郭启勇.新生猪缺氧缺血性脑损伤模型纹状体多巴胺转运蛋白PET/CT显像[J].中华核医学与分子影像学,2013,33(1):56-59
[117] Wang S, Chen Z, Li X, Tang J, Liu C, Zou M, Pan D, Lu C, Xu Y, Xu X, ZhouX, Jin J. The animal biodistribution, safety and validation study of dopaminetransporter PET imaging agent18F-FECNT. Nuclear Science and Techniques [J].2009,20(1):11-16
[118] Naseem A, Rejean L, Serge R. Automated synthesis of11β-methoxy-4,16α-
[16α-18F-difluoroestradiol(4F-M-18F-FES) for estrogen receptor imaging bypositron emission tomography[J]. Nucl Med Biol,2007,34:459-464
[119]鲍伟奇,邱春,管一晖. γ-氨基丁酸A型-苯二氮革受体显像剂在神经系统疾病中的应用[J].国际放射医学核医学杂志,2012,36(1):1-7
[120]张姝,罗世能,邱玲,林建国,夏咏梅,叶万忠.新型骨显像剂99Tcm-BIPrDP的制备及生物学性质研究[J].中华核医学与分子影像学杂志,2012,32(5):379-384
[121]李勇,任映,朱志慧,孙海芸,杨金铎,王蓬文.参桂理中粉急性毒性试验[J].中医药信息,2009,26(6):105-107
[122]张伟,蔡亮,陈跃,黄占文,丁志凌,曹丰,张莉,何菱.双功能制剂99Tcm-Gd-DTPA-DG的制备及在荷瘤裸鼠体内的生物分布[J].中华核医学与分子影像学杂志,2011,31(2):117-120
[123]王慧春,张政伟,刘平,薛方平,谭海波,左传涛,华逢春,赵军,管一晖.阿片受体PET显像剂11C-卡芬太尼的制备及其生物学分布[J].中华核医学与分子影像学杂志,2011,31(1):46-49
[124]张永学,黄钢.核医学[M].北京:人民卫生出版社,2010:40-47
[125]李新刚,赵志刚.群体药代动力学研究进展[J].中国临床药理学杂志,2013,29(1):73-75
[126]李惠义,罗淑荣.液相色谱-质谱联用技术及其在药物代谢研究中的应用[J].国外医学药学分册,1997,24:257-261
[127]张菁,张婴元.去甲万古霉素群体药物动力学与群体药物动力学/药效动力学研究[D].复旦大学,2005
[128]程爱萍,陈绍亮,陈曙光.188Re-HEDP治疗肿瘤骨转移痛药代动力学研究[J].中华核医学与分子影像学杂志,2010,30(4):267-271
[129] Ermer J, Vogel M. Application of hyphenated LC-MS techniques in pharmaceu-tical analysis[J]. Biomed Chromatogr,2000,14:373-376
[130]魏树礼,张强.生物药剂学与药物动力学(第2版)[M].北京:北京大学医学出版社,2007:238-271
[131] Mach R H, Dehdashti F,Wheeler K T. PET Radiotracers for Imaging theProliferative Status of Solid Tumors[J]. PET Clinics,2009,4(1):1-15
[132] Morinaga A, Ono K, Ikeda T, et al. A comparison of the diagnostic sensitivity ofMRI, CBF-SPECT, FDG-PET and cerebrospinal fluidbiomarkers for detectingAlzheimer’s disease in a memory clinie[J]. Dement Geriatr Cogn Disord,2010,30(4):285-29
[133]刘佳佳,刘卫国.帕金森病伴发抑郁发病机制的影像学研究[J].中华临床医师杂志,2013,7(9):3963-3966
[134]牛朝诗,杨艳艳.双靶点注射6-OHDA建立帕金森病大鼠模型并提高成功率[J].立体定向和功能性神经外科杂志,2008,21:257-261
[135]包新民,舒斯云.大鼠脑立体定向图谱[M].北京:人民卫生出版社,1991,12(1):48-54
[136]邓兴力,雷德强,刘如恩,杨智勇,冯忠堂.帕金森病大鼠模型的建立[J].广东医学,2012,33(3):313-315
[137]罗海燕,彭国光.6-羟多巴胺帕金森病动物模型的研究[J].国外医学.神经病学神经外科学分册,1999,26(6):283-286
[138]安备,杜湘珂,霍天龙,张维涛,姚玮,伊险峰. SD大鼠腹腔注射及尾静脉注射18F-FDG PET/CT成像对比研究[J].医学研究杂志,2013,42(5):48-52
[139]曹晓征.正电子发射断层显像检查中显像剂的注射方法比较[J].中国实用医药,2013,8(10):110-111
[140] Wang J, Zuoe T, Jiang Y P, et al.18F-FP-CIT PET imaging and SPM analysis ofdopamine transporters in Parkinson’s disease in various Hoehn&Yahr stages[J].J Neurol,2007,254(2):185-190
[141] Hume S P, Myers R. Dedicated small animal scanners: A new tool for drugdevelopment?[J] Current Pharmaceutical Design,2002,8(16):1497-1511
[142] Difilippo F P, Patel S, Asosingh K, et al. Small animal imaging using clinicalpositron emission tomography/computed tomography and superresolution[J].Mol Imaging,2012,11(3):210-219
[143] Reeve A K, Park T K, Jaros E, et al. Relationship Between Mitochondria andα-Synuclein: A Study of Single Substantia Nigra Neurons [J]. Arch Neurol,2012,69(3):385-393
[144]廖冰,郭纪锋,唐北沙. PINK1基因与帕金森病[J].中华神经科杂志,2007,40(2):136-138
[145]王丽娟,赵洁皓,詹培源.帕金森病患者脑代谢与认知功能的研究[J].中华老年医学杂志,2002,21(5):336-339
[146] Kassiou M, Banati R, Holsinger R M D. Challenges in molecular imaging ofParkinson’s disease: a brief overview[J]. Brain ResBull,2009,78:105-108
[147]马超,王荣福.小动物SPECT/CT的应用进展[J].中国医学装备,2013,10(1):66-68
[148]贾丛康,杨新玲.6-羟基多巴胺所致帕金森病大鼠模型稳定性的研究[J].中国老年学杂志,2009,29(5):521-524
[149]彭峰.姜黄素对6-羟基多巴胺所致大鼠拟帕金森病的保护作用[J].河北北方学院学报,2010,27(6):21-23
[150]李超.多巴胺受体激动剂在帕金森模型中的神经保护机制研究[D].山东,山东大学,2007
[151]罗瑞静,何建成.左旋多巴对帕金森病大鼠纹状体多巴胺转运体的影响[J].医学研究杂志,2011,40(4):40-43
[152]王慧春,左传涛.11C-CFT脑PET显像在早期帕金森病诊断中的临床应用[J].中国临床医学影像杂志,2010,21(4):229-232
[153] Limin Liu, Yong Wang, Bo Li. Evaluation of nigrostriatal damage and itschange over weeks in a rat model of Parkinson's disease: small animal positronemission tomography studies with [11C]β-CFT [J]. Nuclear Medicine andBiology,2009,10:941-947
[154] Magota K, Kubo N, Kuge Y,et al. Performance characterization of the Inveonpreclinical small-animal PET/SPECT/CT system for multimodality imaging[J].Eur J Nucl Med Mol Imaging,2011,38(4):742-752
[155]安备,杜湘珂,霍天龙. SD大鼠腹腔注射及尾静脉注射18F-FDG PET/CT成像对比研究[J].医学研究杂志,2013,42(5):48-52
[156]张维涛,霍天龙,安备,姚玮,伊险峰.正常大鼠18F-FDG PET/CT显像各器官SUV值及CT值分布[J].实验动物科学,2013,30(2):11-13
[157]陈雪祺,王荣福. PET/CT在动物领域的研究进展[J].中国医学装备,2013,10(1):55-59
[158] Aide N, Desmonts C, Beauregard J M, et al. High throughput static and dynamicsmall animal imaging using clinical PET/CT: potential preclinical applications[J]. Eur J Nucl Med Mol Imaging,2010,37(5):991-1001
[159] Guerra P, Rubio J L, Ortuno J E, et al. Performance analysis of a low-cost smallanimal PET/SPECT scanner[J]. Nuclear Instruments&Methods in PhysicsResearch Section a-Accelerators Spectrometers Detectors and AssociatedEquipment,2007,571(1):98-101
[160] Hastings D L, Reader A J, Julyan P J, et al. Performance characteristics of asmall animal PET camera for molecular imaging[J]. Nuclear Instruments&Methods in Physics Research Section a-Accelerators Spectrometers Detectorsand Associated Equipment,2007,573(2):80-83
[161] Well I T, Fox B M. PET/CT in anal cancer-is it worth doing?[J]. Clin Radiol,2012,67(6):535-540
[2]王荣福. PET/CT分子影像新技术应用[M].北京:北京大学医学出版社,2011:750-765
[3] Wahl R L, Beanlands R S. Principle and Practices of PET and PET/CT [M].Philadelphia: Lippincott Williams&Wilkins,2008,15:360-423
[4] Bouchelouche K, Oehr P. Positron Emission Tomography and Positron EmissionTomography/Computerized Tomography of Urological Malignancies: An Updateeview[J]. The Journal of Urology,2008,179(1):34-45
[5] Rajendran J G,Mankoff D A. Beyond Detection: Novel Applications for PETImaging to Guide Cancer Therapy[J]. J Nucl Med,2007,48(6):855-866
[6]王强,王荣福.当代最先进分子影像新技术--PET/MRI[J].中国医疗器械信息,2011,17(4):4-7
[7] Israel O, Kuten A. Early detection of cancer recurrence:18F-FDG PET/CT canmake a difference in diagnosis and patient care[J]. J Nucl Med,2007,48(1):28-35
[8] Buck A K, Herrmann K, Stargardt T, et al. Economic evaluation of PET andPET/CT in oncology: evidence and methodologic approaches[J]. J Nucl Med,2010,51(3):401-412.
[9] Maecke H R, Andre J P.68Ga-PET radiopharmacy:A generator-based alternativeto18F-radiopharmacy[J]. Ernst Schering Res Found Workshop,2007,62(5):215-242
[10]张宝石,周乃康,张锦明,于长海. PET示踪剂的临床应用及研究进展[J].中国医药导刊,2011,13(2):234-237
[11] Lu X,Wang R F. A concise review of current radiopharmaceuticals in tumorangiogenesis imaging[J]. Curr Pharm Des,2012,18(8):1032-1040
[12]贾峰涛,杨星,洪军,张林.医用回旋加速器原理及应用[J].医疗设备信息,2006,21(6):37-38
[13]梁银杏,叶桦.关于我国正电子放射性药品新药注册管理的建议[J].中国新药与临床杂志,2012,31(2):68-71
[14]陈开宇,李新平,陈盛新.正电子放射性药物的应用现状与进展[J].药学实践杂志,2012,30(3):175-177
[15]张锦明,田嘉禾.国内正电于放射性药物发展现状简介[J].同位素,2006,19(4):240-243
[16] Direcks W G, Berndsen S C, Proost N, et al.[18F]FDG and [18F]FLT uptake inhuman breast cancer cells in relation to the effects of chemotherapy: an in vitrostudy[J]. Br J Cancer,2008,99(3):481-487
[17]罗家伦,徐慧琴.11C标记的放射性药物在PET/CT中的应用[J].安徽医学,2009,30(7):728-731
[18]杨敏,潘栋辉,徐宇平,王颂佩.苯甲酰胺类多巴胺D2受体显像剂18F-Fallypride的制备和生物分布[J].核技术,2008,31(5):360-363
[19] Florian A, Timo S S, Sabine H, Ursula S, Bernhard H, Peter R, Cornelius W,Wolfgang A W, Christian W, Philipp T M. Assessment of Striatal DopamineD2/D3Receptor Availability with PET and18F-Desmethoxy-fallypride:Comparison of Imaging Protocols Suited for Clinical Routine[J]. The Journal ofNuclear Medicine,2012,53(10):1558-1564
[20] Jenny C, Elske V, Michel, Tom M, Guy B, Stephan C, Koen V L. Optimized InVivo Detection of Dopamine Release Using18F-Fallypride PET[J]. The Journalof Nuclear Medicine,2012,53(10):1565-1572
[21]孙传金,朱虹,方可元.国产氟多功能模块合成雌激素受体显像剂16α-18F-17β-雌二醇[J].同位素,2012,25(3):156-159
[22] Liu R S, Chou T K, Chang C H, et al. Biodistribution, Phannaeokinetics andPET Imaging of18F-FMISO,18F-FDG and18F-Fac in asareoma andinflammation-bearing mouse model[J]. Nucl Med Biol,2009,36(3):305-312
[23]张锦明,郭喆,田嘉禾,王武尚. β淀粉样蛋白显像剂2-(4-N-11C-甲胺苯基)-6-羟基苯并噻唑的研究[J].中华核医学杂志,2008,28(6):397-399
[24] Divgi C R. Molecular imaging of pulmonary cancer and inflammation[J]. ProcAm Thorac Soc,2009,6(5):464-468
[25] Lee T S, Ahn S H, Moon B S, et al. Comparison of18F-FDG,18F-FET and18F-FLT for differentiation between tumor and inflammation in rats[J]. Nucl82Med Biol,2009,36(6):681-686
[26] Christian F, Gabriele P, Johannes L, Guido B, Christopher U, Paul C, Peter B,Klaus T. The Value of the Dopamine D2/3Receptor Ligand18F-Desmethoxyfallypride for the Differentiation of Idiopathic and Nonidiopathic ParkinsonianSyndromes[J]. The Journal of Nuclear Medicine,2010,51(4):581-587
[27] Kasper B, Egerer G, Gronkowski M, et al. Functional diagnosis of residuallymphomasafter radiochemotherapy with positron emission tomographycomparing FDG-and FLT-PET[J]. Leuk Lymphoma,2007,48(4):746-753
[28]李英华,关锋,代玉银,林承赫.正电子放射性分子显像剂诊断帕金森氏病的研究进展[J]核技术2012,35(3):211-215
[29]李光慧,盛许晶,朱建华.多巴胺受体显像剂125I-DMAIBZM的合成及生物分布实验[J].高等学校化学学报,2010,31(12):2413-2418
[30] Gao M Z, Wang M, Mock B H, Glick B E, Yoder K K, Hutchins G D, Zheng QH. An improved synthesis of dopamine D2/D3receptor radioligands [11C]fallypride and [18F]fallypride[J]. Applied Radiation and Isotopes,2010,68(6):1079-1086
[31]姚志文,丁正同,张政伟,蒋雨平.阿尔茨海默病正电子显像剂11C-6-OH-BTA-1的制备[J].中华核医学杂志,2007,27(6):327-329
[32]周玲,管一晖,薛方平,张政伟,蒋雨平.脑乙酰胆碱酯酶的PET显像剂11C-4-乙酰氧基-N-甲基哌啶在大鼠体内分布的研究[J].中华临床神经科学,2008,16(6):580-584
[33]蒋泉福,吴春英,陆春雄.一种99mTc标记的5-HT1A受体显像剂的合成与标记[J].同位素,2006,19(3):150-153
[34]王明芳,唐刚华,李葆元,王全师,罗志福.11C-PK11195的自动化合成及其生物学分布[J].中华核医学杂志,2008,28(6):400-403
[35]张锦明,桂媛,徐志红,张晓军,向晓辉,田嘉禾.阿片受体显像剂11C-Carfentanil的前体合成及放射性标记[J].核化学与放射化学,2011,33(4):252-256
[36]肖颖,张本恕. UCH-Ll基因多态性与帕金森病的关联研究[J].中华医学遗传学杂志,2008,25(5):586-587
[37]熊慧,张雅坤.帕金森病致病基因DJ-1的研究[J].内科理论与实践,2010,5(5):390-392
[38]杜青青,杨学超,吴娟娟. PD相关基因LRRK2表达调控的初探[J].南通大学学报(医学版),2011,31(6):409-413
[39] Nicholas T V, Jeffrey M M, Alexander K C, James E H, Jogesh M, DhanabalanM R, Jerry N, Richard J D, Mary L S, Bradley T C. High-affinity dopamine D2/D3PET radioligands18F-fallypride and11C-FLB457: A comparison of kineticsin extrastriatal regions using a multiple-injection protocol[J]. Journal of CerebralBlood Flow&Metabolism,2010,30(5):994-1007
[40] Adriana G, Mohammad R M, Cristian C, Eveguen S, Norah M, Jonathan L K,George C, Jogeshwar M.18F-Fallypride PET of Pancreatic Islets: In Vitro and InVivo Rodent Studies[J]. The Journal of Nuclear Medicine,2011,52(7):1125-1132
[41]陈贵兵,吴华,彭添兴.正电子显像剂11C-匹兹堡化合物B的化学合成及其临床应用[J].国际放射医学核医学杂志,2008,32(3):158-161
[42] Aumann K M, Hungerford N L, Coster M J. First enantioselective synthesis ofmethyl (+)-7-methoxyanodendroate, an antitubercular dihydrobenzofuran[J].Tetrahedron Letters,2011,52:6988–6990
[43] Wu Zh. Liang Z Y, Li W, Wang Q A. Synthesis of (±)-Demethylnitidanin,Herpetol and Salvinal as well as Their Glycosyl Derivatives[J]. Chem ResChinese Universities,2011,27(6):949-952
[44] Stichelberger M, Desbouis D, Spiwok V, et al. Synthesis, in vitro and in silicoassessment of organometallic Rhenium(I) and Technetium(I) thymidinecomplexes[J].Journal of Organometallic Chemistry,2007,692(6):1255-1264
[45] KoenV L, Kristien C, Eduard D H, Tjibbede G, WimV. Combined StriatalBinding and Cerebral Influx Analysis of Dynamic11C-Raclopride PETImproves Early Differentiation Between Multiple-System Atrophy andParkinson Disease[J]. The Journal of Nuclear Medicine,2010,51(4):588-595
[46] Monte S, Buchsbaum, Br adley T, et al. D2/D3dopamine receptor binding with
[F]-18fallypride in thalamus and cortex of patients with schizophrenia[J].Schizophrenia Research,2006,85:232-244
[47] Axel R, Erik M, Guido B, Stefan F, Sebastian N, Franz J G, Peter B. Validationof the Octamouse for Simultaneous18F-Fallypride Small-Animal PETRecordings from8Mice[J]. The Journal of Nuclear Medicine,2010,51(10):1576-1583
[48]贾晓娟,王雪晴,许泽清,李慧.两种放射性药物标记法在单光子发射计算机断层显像脑血流灌注显像的应用探讨[J].实用医技杂志,2013,20(4):393-394
[49]曾华辉,张华北.国内心、脑、肿瘤放射性诊断药物研究进展[J].化学进展,2011,23(7):1485-1492
[51]张锦明,田嘉禾,姚树林,丁为民,尹大一,刘伯里.11C-Raclopride的快速制备及生物学评价[J].中华核医学杂志,2008,28(4):227-230
[52]杨敏,徐宇平,潘栋辉,王颂佩,罗世能.18F-Fallypride的自动化合成与小动物PET显像[J].中华核医学杂志,2008,28(4):223-227
[53] Ingo V, Lisa P, Mardjan R, Robert L, Oliver W, Frank R, Peter B, Dean F W.The applicability of SRTM in [18F] fallypride PET investigations: impact ofscan durations[J]. Journal of Cerebral Blood Flow&Metabolism,2011,31(9):1958-1966
[54]张锦明,郑昕,郭喆,田嘉禾.全自动合成3-18F-2-羟基丙烷-2-硝基咪唑及临床前研究[J].首都医科大学学报,2008,29(1):8-11
[55]孙伟张,周克,蒋长青,郭正奎.外周苯二氮卓受体示踪剂18F-SAN的合成[J].西南国防医药,2009,19(9):884-886
[56]李谷才,尹端沚,夏姣云,汪勇先.多巴胺D4受体显像剂18F-FDTP的研制和受体结合分析[J].核化学与放射化学,2008,30(3):167-173
[57] Shao X, Kilbourn M R. A Simple Modification of GE Tracerlab FX C Pro forRapid Sequential Preparation of11C-Carfentanil and11C-Raclopride [J]. ApplRadiat Isot,2009,67:602-605
[58] Windhorst A D, Klein P J, Eisenbarth J, et al.3'-Sulfonylesters of2,5'–anhydro-1-(2-deoxy-[beta]-d-threo-pentofuranosyl)thymine as precursors for thesynthesis of [18F]FLT: syntheses and radiofluorination trials[J]. NuclearMedicine and Biology,2008,35(4):413-423
[59] Celen S, de Groot T, Balzarini J, et al. Synthesis and evaluation of a99mTc-MA-propyl-thymidine complex as a potential probe for in vivo visualization oftumor cell proliferation with SPECT[J]. Nuclear Medicine and Biology,2007,34(3):283-291
[60] Desbouis D, Schubiger P A, Schibli R. Synthesis of tricarbonyl rhenium andtechnetium complexes of a5'-carboxamide5-ethyl-2'-deoxyuridine for selectiveinhibition of herpes simplex virus thymidine kinase1[J]. Journal ofOrganometallic Chemistry,2007,692(6):1340-1347
[61]张锦明,田嘉禾.18F-FDG的质量控制及方法[J].中华核医学杂志,2005,25(6):383-384
[62]张晓军,向晓辉,张锦明,田嘉禾.11C-Carfentanil的质量控制[J].同位素,2013,26(1):29-40
[63]澄清度检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅣB71-71
[64]放射性药品检定法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录Ⅷ123-129
[65]邓怀福,陈萍. PET肿瘤显像剂S-11C-甲基-L-半胱氨酸的制备与质量控制[J].中国医疗前沿,2013,8(7):8-11
[66]许飞,杨敏,潘栋辉.18F-Fallypride标记前体的反相HPLC测定[J].实用临床医药杂志,2008,12(4):44-45
[67]郭莘,史道华.18F-16α-17β-氟雌二醇注射液细菌内毒素检查法的建立[J].中国现代应用药学,2013,30(3):322-326
[68]细菌内毒素检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥE99-102
[69]无菌检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥH103-105
[70]异常毒性检查法.《中华人民共和国药典》2010年版二部[M].北京:中国医药科技出版社,附录ⅥC98-98
[71] Tiantian M, Huihui J, Wen J Y, Wei F, Cheng P, Feng G, Xian Z, Yan P.Preparation and biodistribution of [18F]FP2OP as myocardial perfusion imagingagent for positron emission tomography[J]. Bioorganic&Medicinal Chemistry,2010,18:1312-1320
[72]张贇,吴战宏,李方,朱立.2-18F-A-85380的制备与Micro PET显像[J].同位素,2008,21(1):15-19
[73]张永学,黄钢,匡安仁,李亚明.《核医学》2010年第二版[M].北京:人民卫生出版社,2010,53-54
[74]王荣福,刘萌.活体核素示踪神经受体研究进展[J].北京大学学报,2007,39(5):550-554
[75]钱明理.分子影像学技术及其新进展[J].中国医疗器械杂志,2012,36(4):277-281
[76] Lu C, Jiang Q, Yu H, et al. Preparation and preliminary biological evaluation of99mTc-ANMdU[J]. Nucl Sci Tech,2010,21(2):106-109
[77]谭海波.正电子发射断层(PET)基础与临床研究:11C-左旋千金藤啶碱制备方法及生物学初步评价[J].辽宁中医杂志,2008(1):58-59
[78] Deng H F, Tang G H, Wang H L, et al. Radiosynthesis and evaluation of11C-CYS as an oncologic PET tracer[J]. J Nucl Med,010,51(l2):366-370
[79]张锦明,郭喆,田嘉禾,王武尚. Aβ斑块显像剂11C-苯并呋喃衍生物的研究[J].中华核医学杂志,2007,27(1):38-40
[80]杨敏.18F-Fallypride:一种多巴胺D2受体PET显像剂[J].国外医学.放射医学核医学分册,2003,27(6):259-262
[81] Teng B, Bai Y, Chang Y, et al. Technetium-99m-labeling and synthesis ofthymidine analogs: Potential candidates for tumor imaging[J]. Bioorganic&Medicinal Chemistry Letters,2007,17(12):3440-3444
[82] Eckel F, Herrmann K, Schmidt S, et al. Imaging of proliferation inhepatocellular carcinoma with the in vivo marker18F-fluorothymidine[J]. J NuclMed,2009,50(9):1441-1447
[83] Lee S J, Oh S J, Chi D Y, et al. Simple and highly efficient synthesis of3'-deoxy-3'-[18F]fluorothymidine using nucleophilic fluorination catalyzed byprotic solvent[J]. Eur J Nucl Med Mol Imaging,2007,34(9):1406-1409
[84] Teng B, Bai Y, Chang Y, et al. Technetium-99m-labeling and synthesis ofthymidine analogs: Potential candidates for tumor imaging[J]. Bioorganic&Medicinal Chemistry Letters,2007,17(12):3440-3444
[85] Kato T, Shinoda J, Nakayama N, et al. Metabolite assessment of gliomasusing1IC-methionine,18F-fluorodeoxyglucose and1IC-choline Positron emissiontomography[J]. AJNR,2008,29(6):1176-1118
[86] Chen Z P, Wang S P, Li X M, Liu C Y, Tang J, Luo S N, Cao G X, Zhang L F,Jin J. A one-step automated high-radiochemical-yield synthesis of18F-FECNTfrom mesylate precursor [C].55thannual meeting of Society of NuclearMedicine. New Orlean, USA. J Nucl Med,2008,49(Supplement1):306P
[87] Chen Z P, Wang S P, Tang J, Li X M, Liu C Y, Xu X J, Cao G X. Simplifiedmethod for determining radiochemical purity of99mTc-TRODAT-1[J]. Journal ofRadioanalytical and Nuclear Chemistry,2008,277(3):591-594
[88] Chen Z P, Wang S P, Li X M, Liu C Y, Tang J, Cao G X, Luo S N, Zhang L F,Jin J. A one-step automated high-radiochemical-yield synthesis of18F-FECNTfrom mesylate precursor[J]. Applied Radiation and Isotopes,2008,26(12):1881-1885
[89]彭程,牟甜甜,赵祚全,马云川,张现忠.18F-标记哒嗪酮类似物的制备及其在小鼠体内的生物分布[J].同位素,2013,26(1):23-28
[90] Chen W, Delaloye S, Silverman D H, et al. Predicting treatment response ofmalignant gliomas to bevacizumab and irinotecan by imaging proliferation with
[18F]fluorothymidine positron emission tomography: a pilot study[J]. J ClinOncol,2007,25(30):4714-4721
[91] SFDA. Good preparation practice of positron radioactive drugs in medicalinstitution [S].2006
[92]杨志,朱华.新型PET核素68Ga标记D-脱氧葡萄糖的合成及生物学评价[J].化学学报,2012,70(9):1066-1072
[93]余大富,杨吉生.11C-PIB PET对阿尔茨海默病的诊断价值[J].中华核医学杂志,2009,29(3):214-216
[94]杨洋,崔孟超,汤睿昆,吴瑞,朱霖,张华北. Re/99Tcm(CO)3+－二苯基二氮烯类化合物Ａβ显像剂的制备以及生物评价[J].同位素,2013,26(2):65-71
[95] Teng B, Wang S, Fu Z, et al. Semiautomatic synthesis of3'-deoxy-3'-[18F]fluoro-thymidine using three precursors[J]. Applied Radiation and Isotopes,2006,64(2):187-193
[96]刘昌孝,刘定远.药物动力学概论[M].北京:中国学术出版社,1984:170-269
[97]赵占中.硝唑尼特在山羊体内的药物代谢动力学及毒理学研究[D].北京:中国农业科学院,2009
[98]曹国宪,周杏琴,颜成龙,张建康,钦晓峰.受体显像剂99mTc-NCAM在小鼠脑组织中的药物代谢动力学研究[J].核技术,2010,33(10):797-800
[99] Van L K, Varrone A, Booij J, et al. European Association of Nuclear Medicineguidelines for brain neurotransmission SPECT/PET using dopamine D2receptorligands[J]. Eur J Nucl Med Mol Imaging,2010,37:434–442
[100] Shi J, Zhao L Y, CopersinoM L,et al. PET imaging of dopamine transporteranddrug craving duringmethadone maintenance treatment and after prolongedabstinence in heroin users[J]. Eur Jpharmacol,2008,579:160-166
[101]陈正平,王颂佩,李晓敏,刘春仪,唐婕.18F-FECNT的生物分布特性及小动物PET显像研究[J].中华核医学杂志,2009,29(3):181-184
[102]邓怀福,文富华,唐刚华，孟悛非.18F-氟代乙酸盐自动化合成及其动物实验研究[J].中山大学学报（医学科学版）,2011,32(1):99-103
[103]王洪震,贾正平,郝彦明,钱荣勋,董启榕,徐又佳.188Re-碘化油-羧甲基壳聚糖-纳米微粒在荷S180肉瘤小鼠体内分布与代谢[J].中国组织工程研究与临床康复,2011,15(51):9603-9607
[104]王新艳,张政伟,蒋雨平,孔艳艳,桂媛,胡名扬,华逢春,管一晖. β淀粉样蛋白PET显像剂11C-DPOD的制备及其在动物体内的分布[J].中国临床神经科学,2013,21(1):12-18
[105] Huang Y R, Shih J M, Chang K W, et al.[123I]-Epidepride neuroimaging ofdopamine D2/D3receptor in chronic MK-801-induced rat schizophrenia model[J]. Nucl Med Biol,2012,39(6):826-832
[106]鲍晓,王明伟,徐俊彦,郑宇佳,蒋津津,章英剑.新型18F-RGD二聚体的正常生物分布及U87MG荷瘤裸鼠小动物PET/CT显像研究[J].中国癌症杂志,2010,23(6):408-412
[107]戈宏焱,陈博,许丹,李有田,李洋.柴胡皂苷A对抑郁模型大鼠脑中单胺类神经递质及其代谢产物含量的影响[J].高等学校化学学报,2008,29(8):1535-1538
[108] Laforest R, Longford D, Siegel S, et al. Performance evaluation of the microPET(R)FOCUS-F120[J]. Ieee Transactions on Nuclear Science,2007,54(1):42-49
[109] Wang H, Cai W, Chen K, et a1. A new PET tracer specific for vascularendothelial growth factor receptor2[J]. Eur J Nucl Med Mol Imaging,2007,34(12):2001-2010
[110] Jacobson O, Zhu L, MaY, et al. Rapid and simple onestep F-18labeling ofpeptides[J]. Bioconjug Chem,2011,22(3):422-428
[111]潘栋辉,杨敏,徐宇平.18F-RGD环肽二聚体的自动化合成及小动物PET显像[J].中华核医学与分子影像杂志,2012,32(2):90-94
[112]贺立娟,王玉来,郭蓉娟. PET在神经精神疾病领域的应用进展[J].中华中医药学刊[J].2012,30(12):2639-2641
[113] Shankar V, Lilja S, Brigitte V. A broad overview of positron emissiontomography radiopharmaceuticals and clinical applications: What is new?[J].Semin Nucl Med,2011,41:246-250
[114]陆春雄,王正武,蒋泉福.18F-FLT的制备及其microPET显像[J].同位素,2008,21(3):145-149
[115] Been L B, Elsinga P H, de Vries J, et al. Positron emission tomography inpatients with breast cancer using18F-3'-deoxy-3'-fluoro-l-thymidine(18F-FLT)--a pilot study[J]. European Journal of Surgical Oncology,2006,32(1):39-43
[116]张妍芬,王晓明,王晓煜,曹礼,郭启勇.新生猪缺氧缺血性脑损伤模型纹状体多巴胺转运蛋白PET/CT显像[J].中华核医学与分子影像学,2013,33(1):56-59
[117] Wang S, Chen Z, Li X, Tang J, Liu C, Zou M, Pan D, Lu C, Xu Y, Xu X, ZhouX, Jin J. The animal biodistribution, safety and validation study of dopaminetransporter PET imaging agent18F-FECNT. Nuclear Science and Techniques [J].2009,20(1):11-16
[118] Naseem A, Rejean L, Serge R. Automated synthesis of11β-methoxy-4,16α-
[16α-18F-difluoroestradiol(4F-M-18F-FES) for estrogen receptor imaging bypositron emission tomography[J]. Nucl Med Biol,2007,34:459-464
[119]鲍伟奇,邱春,管一晖. γ-氨基丁酸A型-苯二氮革受体显像剂在神经系统疾病中的应用[J].国际放射医学核医学杂志,2012,36(1):1-7
[120]张姝,罗世能,邱玲,林建国,夏咏梅,叶万忠.新型骨显像剂99Tcm-BIPrDP的制备及生物学性质研究[J].中华核医学与分子影像学杂志,2012,32(5):379-384
[121]李勇,任映,朱志慧,孙海芸,杨金铎,王蓬文.参桂理中粉急性毒性试验[J].中医药信息,2009,26(6):105-107
[122]张伟,蔡亮,陈跃,黄占文,丁志凌,曹丰,张莉,何菱.双功能制剂99Tcm-Gd-DTPA-DG的制备及在荷瘤裸鼠体内的生物分布[J].中华核医学与分子影像学杂志,2011,31(2):117-120
[123]王慧春,张政伟,刘平,薛方平,谭海波,左传涛,华逢春,赵军,管一晖.阿片受体PET显像剂11C-卡芬太尼的制备及其生物学分布[J].中华核医学与分子影像学杂志,2011,31(1):46-49
[124]张永学,黄钢.核医学[M].北京:人民卫生出版社,2010:40-47
[125]李新刚,赵志刚.群体药代动力学研究进展[J].中国临床药理学杂志,2013,29(1):73-75
[126]李惠义,罗淑荣.液相色谱-质谱联用技术及其在药物代谢研究中的应用[J].国外医学药学分册,1997,24:257-261
[127]张菁,张婴元.去甲万古霉素群体药物动力学与群体药物动力学/药效动力学研究[D].复旦大学,2005
[128]程爱萍,陈绍亮,陈曙光.188Re-HEDP治疗肿瘤骨转移痛药代动力学研究[J].中华核医学与分子影像学杂志,2010,30(4):267-271
[129] Ermer J, Vogel M. Application of hyphenated LC-MS techniques in pharmaceu-tical analysis[J]. Biomed Chromatogr,2000,14:373-376
[130]魏树礼,张强.生物药剂学与药物动力学(第2版)[M].北京:北京大学医学出版社,2007:238-271
[131] Mach R H, Dehdashti F,Wheeler K T. PET Radiotracers for Imaging theProliferative Status of Solid Tumors[J]. PET Clinics,2009,4(1):1-15
[132] Morinaga A, Ono K, Ikeda T, et al. A comparison of the diagnostic sensitivity ofMRI, CBF-SPECT, FDG-PET and cerebrospinal fluidbiomarkers for detectingAlzheimer’s disease in a memory clinie[J]. Dement Geriatr Cogn Disord,2010,30(4):285-29
[133]刘佳佳,刘卫国.帕金森病伴发抑郁发病机制的影像学研究[J].中华临床医师杂志,2013,7(9):3963-3966
[134]牛朝诗,杨艳艳.双靶点注射6-OHDA建立帕金森病大鼠模型并提高成功率[J].立体定向和功能性神经外科杂志,2008,21:257-261
[135]包新民,舒斯云.大鼠脑立体定向图谱[M].北京:人民卫生出版社,1991,12(1):48-54
[136]邓兴力,雷德强,刘如恩,杨智勇,冯忠堂.帕金森病大鼠模型的建立[J].广东医学,2012,33(3):313-315
[137]罗海燕,彭国光.6-羟多巴胺帕金森病动物模型的研究[J].国外医学.神经病学神经外科学分册,1999,26(6):283-286
[138]安备,杜湘珂,霍天龙,张维涛,姚玮,伊险峰. SD大鼠腹腔注射及尾静脉注射18F-FDG PET/CT成像对比研究[J].医学研究杂志,2013,42(5):48-52
[139]曹晓征.正电子发射断层显像检查中显像剂的注射方法比较[J].中国实用医药,2013,8(10):110-111
[140] Wang J, Zuoe T, Jiang Y P, et al.18F-FP-CIT PET imaging and SPM analysis ofdopamine transporters in Parkinson’s disease in various Hoehn&Yahr stages[J].J Neurol,2007,254(2):185-190
[141] Hume S P, Myers R. Dedicated small animal scanners: A new tool for drugdevelopment?[J] Current Pharmaceutical Design,2002,8(16):1497-1511
[142] Difilippo F P, Patel S, Asosingh K, et al. Small animal imaging using clinicalpositron emission tomography/computed tomography and superresolution[J].Mol Imaging,2012,11(3):210-219
[143] Reeve A K, Park T K, Jaros E, et al. Relationship Between Mitochondria andα-Synuclein: A Study of Single Substantia Nigra Neurons [J]. Arch Neurol,2012,69(3):385-393
[144]廖冰,郭纪锋,唐北沙. PINK1基因与帕金森病[J].中华神经科杂志,2007,40(2):136-138
[145]王丽娟,赵洁皓,詹培源.帕金森病患者脑代谢与认知功能的研究[J].中华老年医学杂志,2002,21(5):336-339
[146] Kassiou M, Banati R, Holsinger R M D. Challenges in molecular imaging ofParkinson’s disease: a brief overview[J]. Brain ResBull,2009,78:105-108
[147]马超,王荣福.小动物SPECT/CT的应用进展[J].中国医学装备,2013,10(1):66-68
[148]贾丛康,杨新玲.6-羟基多巴胺所致帕金森病大鼠模型稳定性的研究[J].中国老年学杂志,2009,29(5):521-524
[149]彭峰.姜黄素对6-羟基多巴胺所致大鼠拟帕金森病的保护作用[J].河北北方学院学报,2010,27(6):21-23
[150]李超.多巴胺受体激动剂在帕金森模型中的神经保护机制研究[D].山东,山东大学,2007
[151]罗瑞静,何建成.左旋多巴对帕金森病大鼠纹状体多巴胺转运体的影响[J].医学研究杂志,2011,40(4):40-43
[152]王慧春,左传涛.11C-CFT脑PET显像在早期帕金森病诊断中的临床应用[J].中国临床医学影像杂志,2010,21(4):229-232
[153] Limin Liu, Yong Wang, Bo Li. Evaluation of nigrostriatal damage and itschange over weeks in a rat model of Parkinson's disease: small animal positronemission tomography studies with [11C]β-CFT [J]. Nuclear Medicine andBiology,2009,10:941-947
[154] Magota K, Kubo N, Kuge Y,et al. Performance characterization of the Inveonpreclinical small-animal PET/SPECT/CT system for multimodality imaging[J].Eur J Nucl Med Mol Imaging,2011,38(4):742-752
[155]安备,杜湘珂,霍天龙. SD大鼠腹腔注射及尾静脉注射18F-FDG PET/CT成像对比研究[J].医学研究杂志,2013,42(5):48-52
[156]张维涛,霍天龙,安备,姚玮,伊险峰.正常大鼠18F-FDG PET/CT显像各器官SUV值及CT值分布[J].实验动物科学,2013,30(2):11-13
[157]陈雪祺,王荣福. PET/CT在动物领域的研究进展[J].中国医学装备,2013,10(1):55-59
[158] Aide N, Desmonts C, Beauregard J M, et al. High throughput static and dynamicsmall animal imaging using clinical PET/CT: potential preclinical applications[J]. Eur J Nucl Med Mol Imaging,2010,37(5):991-1001
[159] Guerra P, Rubio J L, Ortuno J E, et al. Performance analysis of a low-cost smallanimal PET/SPECT scanner[J]. Nuclear Instruments&Methods in PhysicsResearch Section a-Accelerators Spectrometers Detectors and AssociatedEquipment,2007,571(1):98-101
[160] Hastings D L, Reader A J, Julyan P J, et al. Performance characteristics of asmall animal PET camera for molecular imaging[J]. Nuclear Instruments&Methods in Physics Research Section a-Accelerators Spectrometers Detectorsand Associated Equipment,2007,573(2):80-83
[161] Well I T, Fox B M. PET/CT in anal cancer-is it worth doing?[J]. Clin Radiol,2012,67(6):535-540
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