在转基因痴呆小鼠及猕猴[~(11)C]MP4A PET显像脑乙酰胆碱酯酶活性

目的:应用PET诊断显像剂[~(11)C]4-乙酰氧基-N-甲基哌啶([~(11)C]MP4A)对转基因痴呆小鼠、老龄小鼠及猕猴进行活体脑乙酰胆碱酯酶(AChE)活性PET显像研究。方法:小鼠经静脉注射[~(11)C]MP4A后进行PET/CT扫描,采集图像测量并计算出各感兴趣区域放射总量百分比(%ID),分析两组小鼠间及猕猴的PET显像差异与特点。扫描后即刻分离小鼠大脑、小脑和脑干,称重并测定~(11)C计数,计算放射性摄取率(%ID/g),比较两组小鼠脑放射性摄取率分布差异。结果:两组小鼠放射性显像清晰,脑放射性聚集对称。转基因痴呆鼠脑中放射性聚集较老龄鼠稀疏。转基因小鼠和老龄鼠大脑平均放射性摄取率值分别为1.49%ID/g和2.62%ID/g,差异有统计学意义(P=0.025)。猕猴脑内放射性显像清晰,放射性物质对称浓聚于皮质下,皮质聚集中等。结论:小鼠和正常猕猴[~(11)C]MP4A PET显像清晰,放射性物质对称分布于皮质下,[~(11)C]MP4A可以活体显像脑AChE的活性。     

乙酰胆碱酯酶活性的PET显像剂-[^11C]MP4A的制备

目的：合成能反映脑乙酰胆碱酯酶活性的PET显像剂[^11C]4-乙酰氧基-N-甲基哌啶（[^11C]MP4A）的前体4-乙酰氧基哌啶（P4A），制备[^11C]MP4A。方法：合成MP4A前体P4A，利用[^11C]碘代甲烷合成模块合成的[^11C]碘代甲烷（[^11C]CH3I）直接与P4A反应制备[^11C]MP4A，或将[^11C]CH3I通过三氟甲基磺酸银柱转化为[^11C]-三氟甲基磺酸甲酯（[^11C]-Triflate-CH3）后再与P4A反应制备[^11C]MP4A。结果：P4A化学纯度达99％以上。采用[^11C]-Triflate-CH3制备的[^11C]MP4A放化纯〉98％，轰击结束后（EOB）放射合成时间为20min，校正衰变后产率为40％-55％。结论：采用[^11C]-Triflate-CH3制备的[^11C]MP4A放化纯度高，产率高。     

脑乙酰胆碱酯酶活性PET显像剂[11C]4-乙酰氧基-N-甲基哌啶纯化及鉴定的研究

目的 研究脑乙酰胆碱酯酶(AChE)活性PET显像剂[11C]4-乙酰氧基-N-甲基哌啶(MP4A)的纯化及其鉴定方法.方法 用半制备高效液相色谱(HPLC)法,用强极性半制备柱Platinum EPS C-18分离纯化[11C]MP4A粗产品,流动相使用乙酸铵-乙醇二元体系,一步法收集[11C]MP4A.用UV串联电化学(ECD)法和同位素法检测鉴定终产物[11C]MP4A的化学纯度及放射性纯度.结果 用此纯化方法,前体(P4A)的保留时间为(2.5±0.3)min;MP4A的保留时间为(9.0±0.3)min;MP4A与P4A及其他杂质完全分离.纯化后的[11C]MP4A终产物经ECD和同位素法检测鉴定,其化学纯度达99%以上,放射纯度达100%.结论 用半制备HPLC法可获得高纯度的[11C]MP4A,用ECD和同位素法鉴定准确率高,且本纯化、鉴定方法耗时短,有助于提高[11C]MP4A的质量和产量.     

β淀粉样蛋白显像剂[^11C]6-OH-BTA-1在转基因型痴呆鼠和正常猴体内的分布

目的：观察脑内β淀粉样蛋白的PET显像剂[^11C]6-OH-BTA-1在SD大鼠体内药动学特征和对转基因痴呆小鼠、猕猴的活体显像。方法：①SD大鼠给药后不同时间点（每个时间点为一组）,分别取血和心、肝、脾、肺、肾、脑（额叶、颞顶叶、枕叶、小脑和脑干）脏器,测定放射性计数并称重,计算经体重校正后每个时间点的每克组织注射剂量百分数（％ID-kg／g）。②转基因型痴呆小鼠和猕猴静脉给药后,使用PET／CT扫描,勾画出在各器官容积感兴趣区（VOI）的放射性计数。结果：①给药后,SD大鼠血和肺放射性早期摄取较多,但清除迅速,主要通过肝脏代谢。注射后20min时的器官内放射性分布从高至低分别为：肝、肺、肾、血、脾、心。②转基因型痴呆小鼠、正常老龄对照组小鼠和正常猕猴均有明显的肝脏放射性聚积,肾脏中度显影,但脑内未见两组鼠间差异有统计学意义。结论：[^11C]6-OH-BTA-1通过血液循环,快速在SD大鼠、转基因型痴呆小鼠和猕猴脑内清除。     

[~(18)F]FDG脑代谢联合[~(11)C]CFT脑多巴胺转运体PET显像对帕金森病的临床研究

目的探讨[18F]FDG脑代谢联合[11C]CFT脑多巴胺转运体(DAT)正电子发射断层显像(PET)对帕金森病(PD)诊断及病情严重度评估的应用价值。方法对30例PD患者(PD组)进行[18F]FDG脑代谢显像和[11C]CFT脑DAT PET显像检查,同时采用帕金森病统一评分量表第三部分(UPDRSⅢ)的运动评分和Hoehn-Yahr(H-Y)分期对纳入研究PD患者的临床症状进行评分,分析[18F]FDG PET、[11C]CFT PET和临床评分之间的相关性。选取年龄匹配的健康受试者10名为对照组。结果 [18F]FDG PET提示PD组普遍存在苍白球、丘脑、脑干、小脑、感觉运动皮质区代谢增强和运动前皮质、顶枕区代谢减弱的PD相关代谢模式(PDRP),PDRP评分与发病年龄和H-Y分期评分存在显著正相关。[11C]CFT PET提示PD组存在尾状核、壳核DAT摄取值较对照组下降,纹状体DAT摄取值和UPDRSⅢ评分、H-Y分期和PDRP评分存在显著负相关。结论 [11C]CFT与[18F]FDG PET显像联合检查有助于PD诊断和病情严重度的评估。     

急性脑缺血再灌注大鼠不同脑区乙酰胆碱酯酶活性的变化

本文旨在探讨胆碱能神经在脑缺血再灌注时的变化和意义。采用双侧颈总动脉夹闭（CCAO）的大鼠脑缺血动物模型,用改良的Ellman法测定大脑皮层、海马、间脑、纹状体和脑子五个脑区乙酰胆碱酯酶（AChE）活性,观察脑缺血30分钟和再灌注30分钟不同脑区AChE活性的变化。结果发现：在生理状态下不同胞区AChE活性不同,纹状体最高（181．8±1．7μ／g）,皮层最低（24．1±0．4μ／g）,CCAO30分钟皮层、海马、间脑、纹状体的AChE活性均明显下降,较正常大鼠分别降低278％、26．3％、16．9％、23．6％（P＜0．01）,再灌注30分钟后分别回升18.4％、17.6％、10．2％、23．7％（P＜0．01）。而脑干在缺血和再灌注中无显著变化。结果提示不同胞区胆碱能活性程度不同;脑AChE活性对缺血和再灌注是敏感的,推测胆碱能神经可能在缺血性脑损伤中起重要作用。     

局部激素缓释片应用对脑内血肿清除后脑水肿的影响

目的研究局部应用地塞米松缓释片对兔脑内血肿清除术后脑水肿的影响。方法32只兔子随机分为A（对照组）和B（治疗组）两组并应用自体血注射法建立脑内血肿模型。A组行常规血肿清除术；B组于血肿清除术后，在血肿残腔内置入地塞米松缓释片。检测两组兔脑组织含水量和血清髓鞘碱性蛋白（MBP）水平并比较。结果A、B两组患侧大脑半球含水量分别为（83．61±0．62）％和（81．53±0．59）％，B组显著低于A组（P〈0．05）。A、B两组血清MBP分别为（6．18±2．13）μg／L和（3．35±1．29）μg／L，均高于正常对照值（1．78±0．76）μg／L，且A组显著高于B组（P〈0．05）。结论脑内血肿清除术后脑组织含水量及血清MBP增高，局部应用地塞米松缓释片后显著降低，提示该方法是预防和治疗脑内血肿清除术后脑水肿的有效方法。     

自制和国外的6-OH-BTA-0放射性核素标记效果的比较

目的：观察放射性核素标记的不同来源的6-OH-BTA-0，比较制备的阿尔茨海默病（AD）PET显像剂[^11C]6-OH-BTA-1的效果。方法：分别使用两种来源的6-OH-BTA-0，以同样的反应条件，通过^11C-Triflate-CH3行放射性核素^11C标记成[^11C]6-OH-BTA-1，应用C18cartridge柱提纯产品。结果：两种不同来源的6-OH-BTA-0，标记出产品[^11C]6-OH-BTA-1的效果没有明显差异。按照加速器生产925MBq“c—Triflate—CH3计算，未校正“c衰变的情况下，无色澄清[^11C]6-OH-BTA-1注射液的产率均在36％-44％，放化纯92％-93％。结论：自制的6-OH-BTA-0可以在ADPET显像剂[^11C]6-OH-BTA-1研究中使用。     

心房颤动引起心源性脑栓塞颅内梗死灶空间分布特点

目的：探讨心房颤动引起心源性脑栓塞颅内梗死灶空间分布特点。方法：回顾性分析66例由心房颤动引起心源性脑栓塞患者早期弥散加权成像（DWI）的特征。结果：66例患者中有1例患者DWI上未见病灶,65例患者DWI上可见本次责任病灶。多发梗死灶患者有21／65例,占32．31％;双侧前循环供血区同时梗死7／21例,占多发脑梗死灶患者的33．33％;45例单独前循环供血区梗死患者中,左侧前循环供血区梗死23／45例（51．11％）,右侧前循环供血区梗死15／45例（33．33％）,脑栓塞以左侧居多;前循环供血区中大脑中动脉（MCA）供血区发生栓塞的概率最大（35／45例,77．78％）,35例大脑MCA供血区梗死患者中,皮质下梗死[9／35例（25．71％）]和皮质-皮质下梗死[22／35例（62．86％）1的患者例数明显多于皮质区梗死[4／35例（11．43％）]患者。结论：心房颤动引起心源性脑栓塞的脑内病灶左侧脑多见,大脑中动脉更易发生,皮质下和皮质-皮质下梗死多于皮质区梗死。     

MP4A-PET在阿尔茨海默病中的应用

乙酰六氢吡啶酯(MP4A)对乙酰胆碱酯酶(AchE)具有较高的选择性,是用PET测定活体AchE活性的理想的示踪剂。[11C]MP4A-PET的分析方法主要有三种:标准房室模型分析法(compartment analysis)、图形分析法(shapeanalysis)、组织参考性线性最小平方法(reference tissue-based linear least squares analysis,RLS)。AchE活性的降低是阿尔茨海默病(AD)的重要特征,因此N-[11C]-MP4A-PET可应用于AD的早期诊断、发病机制、药物疗效评价等方面。     

Further evaluation of [11C]MP‐10 as a radiotracer for phosphodiesterase 10A: PET imaging study in rhesus monkeys and brain tissue metabolite analysis

[¹¹C]MP‐10 is a potent and specific PET tracer previously shown to be suitable for imaging the phosphodiesterase 10A (PDE10A) in baboons with reversible kinetics and high specific binding. However, another report indicated that [¹¹C]MP‐10 displayed seemingly irreversible kinetics in rhesus monkeys, potentially due to the presence of a radiolabeled metabolite capable of penetrating the blood‐brain‐barrier (BBB) into the brain. This study was designed to address the discrepancies between the species by re‐evaluating [¹¹C]MP‐10 in vivo in rhesus monkey with baseline scans to assess tissue uptake kinetics and self‐blocking scans with unlabeled MP‐10 to determine binding specificity. Ex vivo studies with one rhesus monkey and 4 Sprague‐Dawley rats were also performed to investigate the presence of radiolabeled metabolites in the brain. Our results indicated that [¹¹C]MP‐10 displayed reversible uptake kinetics in rhesus monkeys, albeit slower than in baboons. Administration of unlabeled MP‐10 reduced the binding of [¹¹C]MP‐10 in a dose‐dependent manner in all brain regions including the cerebellum. Consequently, the cerebellum appeared not to be a suitable reference tissue in rhesus monkeys. Regional volume of distribution (V_T) was mostly reliably derived with the multilinear analysis (MA1) method. In ex vivo studies in the monkey and rats only negligible amount of radiometabolites was seen in the brain of either species. In summary, results from the present study strongly support the suitability of [¹¹C]MP‐10 as a radiotracer for PET imaging and quantification of PDE10A in nonhuman primates. Synapse 69:86–95, 2015. © 2014 Wiley Periodicals, Inc.     

VMAT2 binding is elevated in dopa-responsive dystonia: visualizing empty vesicles by PET

Dopa-responsive dystonia (DRD) is a lifelong disorder in which dopamine deficiency is not associated with neuronal loss and therefore it is an ideal human model for investigating the compensatory changes that occur in response to this biochemical abnormality. Using positron emission tomography (PET), we examined the (+/-)-alpha-[(11)C]dihydrotetrabenazine ([(11)C]DTBZ) binding potential of untreated DRD patients and normal controls. Two other PET markers of presynaptic nigrostriatal function, d-threo-[(11)C]methylphenidate ([(11)C]MP) and 6-[(18)F]fluoro-L-dopa ([(18)F]-dopa), and [(11)C]raclopride were also used in the study. We found increased [(11)C]DTBZ binding potential in the striatum of DRD patients. By contrast, no significant changes were detected in either [(11)C]MP binding potential or [(18)F]-dopa uptake rate constant. In addition, we found evidence for increased dopamine turnover in one DRD patient by examining changes in [(11)C]raclopride binding potential in relation to levodopa treatment. We propose that the increase in [(11)C]DTBZ binding likely reflects the dramatic decrease in the intravesicular concentration of dopamine that occurs in DRD; upregulation of vesicular monoamine transporter type 2 (VMAT2) expression may also contribute. Our findings suggest that the striatal expression of VMAT2 (as estimated by [(11)C]DTBZ binding) is not coregulated with dopamine synthesis. This is in keeping with a role for VMAT2 in other cellular processes (i.e., sequestration and release from the cell of potential toxic products), in addition to its importance for the quantal release of monoamines.     

In vivo detection of short- and long-term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain

The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [¹¹C](+)McN 5652, a potent 5-HT transporter ligand, as well as [¹¹C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [¹¹C](+)McN5652, [¹¹C](−)McN5652 (the inactive enantiomer of the active enantiomer [¹¹C](+)McN5652) and [¹¹C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [¹¹C](+)McN 5652, but not with [¹¹C](−)McN5652 or [¹¹C]RTI-55. Reductions in specific [¹¹C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (−)[¹¹C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [¹¹C](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [¹¹C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects. Synapse 29:183–192, 1998. © 1998 Wiley-Liss, Inc.     

First visualization of adenosine A(2A) receptors in the human brain by positron emission tomography with [11C]TMSX

[11C]TMSX is a new positron emission tomography (PET) radioligand that provides visualization of adenosine A(2A) receptors (A(2A)Rs) in the brain, heart and skeletal muscle. Here we report on the first visualization of the A(2A)Rs in the human brain by PET and [11C]TMSX in a male healthy volunteer, compared with the adenosine A1 receptors (A1Rs) and dopamine D2 receptors (D2Rs) which were measured by PET with [11C]MPDX and [11C]raclopride, respectively. The distribution volume (DV) of [11C]TMSX in the baseline was relatively high in the head of caudate nucleus, putamen, and thalamus and relatively low in the cortical regions. Infusion of theophylline, a nonselective A(2A)R antagonist (Ki for A(2A)Rs = 16000 nM for theophylline vs 5.9 nM for TMSX), slightly reduced the DVs in the head of caudate nucleus (8.0% reduction) and putamen (4.5% reduction), but not in the other regions having much lower levels of A(2A)Rs, demonstrating the A(2A)R-specific binding of [11C]TMSX. On the other hand, the A1Rs were widely distributed in the whole brain except for the cerebellum, while the binding potential of [11C]raclopride was predominantly high in the striatum. We concluded that [11C]TMSX is an applicable PET ligand for mapping the A(2A)Rs in the caudate nucleus and putamen in clinical studies because of no availability of other radioligands until now. The [11C]TMSX PET is of great interest for studying the pathophysiology of neurological and psychiatric disorders together with the [11C]raclopride PET for D2Rs evaluation and/or the [11C]MPDX PET for A1Rs evaluation.     

Age and severity of nigrostriatal damage at onset of Parkinson's disease

The clinical evolution of Parkinson's disease (PD) is known to be partly dependent on the age of onset. For example, motor complications associated with chronic dopaminomimetic treatment occur more often in younger patients. However, few attempts have been made to characterize the functional pathological differences underlying this age effect. We investigated the relationship between age and severity of nigrostriatal damage at onset of PD. Twenty patients with early PD (symptom duration 相似文献   

In vivo evaluation of N‐[18F]fluoroethylpiperidin‐4ylmethyl acetate in rats compared with MP4A as a probe for measuring cerebral acetylcholinesterase activity

[¹¹C]MP4A is an established radioprobe for quantification of cerebral acetylcholinesterase (AChE) activity by positron emission tomography (PET) based on the kinetics of AChE‐mediated metabolism and metabolite trapping. It has been used to assess the deficiency in cholinergic innervation in the brain of patients with dementia. Because ¹⁸F has a longer half‐life than ¹¹C, ¹⁸F‐labeled derivatives of [¹¹C]MP4A allow delivery of the probe to other PET centers, making AChE measurement more widely applicable. Previously, N‐[¹⁸F]fluoroethylpiperidin‐4ylmethyl acetate ([¹⁸F]FEP‐4MA) showed that the ¹⁸F‐labeled analog of MP4A possessed desirable properties for the quantification of cerebral AChE activity by PET. Here, we evaluated the in vivo kinetics of [¹⁸F]FEP‐4MA and validated the responsiveness of brain uptake to AChE activity based on a mathematical model derived from the AChE‐mediated trapping rationale and compared it with MP4A in rats. Almost all radioactivity in the brain was composed of [¹⁸F]FEP‐4MA and the hydrolyzed metabolite at 0–60‐min postinjection. When the authentic radioprobe was not observed in the brain, the regional ¹⁸F uptake in the brain correlated well with regional MP4A uptake, and the elimination rate of ¹⁸F from the brain was higher than that of the metabolite of MP4A. The responsiveness of regional ¹⁸F uptake in the brain was examined by simultaneous assay of ¹⁸F concentration, relative blood flow, and AChE activity. Regional ¹⁸F uptake correlated with regional AChE activity as well as that of MP4A. Therefore, we concluded that [¹⁸F]FEP‐4MA would be applicable to clinical PET study for quantifying cerebral AChE activity. Synapse 64:209–215, 2010. © 2009 Wiley‐Liss, Inc.     

Differential effects of stress on [11C]raclopride and [11C]MNPA binding to striatal D2/D3 dopamine receptors: A PET study in conscious monkeys

It has been reported that stress and facilitation of dopamine neuronal system are closely related. In the present study, the effects of stress on the binding of antagonist‐based [¹¹C]raclopride and agonist‐based (R)‐2‐CH3O‐N‐n‐ propylnorapomorphine ([¹¹C]MNPA) to D₂/D₃ receptors were evaluated in the striatum of conscious monkey brain. The stress state assessed from plasma cortisol level was negatively correlated with [¹¹C]raclopride binding as expected. It was noteworthy that [¹¹C]MNPA binding exhibited a positive correlation with stress state; thus, the animals with higher cortisol levels showed higher binding to D₂/D₃ receptors. Synapse 65:84–89, 2011. © 2010 Wiley‐Liss, Inc.     

In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET

The number of functionally active synapses provides a measure of neural integrity, with reductions observed in neurodegenerative disorders. [11C]UCB-J binds to synaptic vesicle 2A (SV2A) transmembrane protein located in secretory vesicles. We aimed to assess [11C]UCB-J PET as an in vivo biomarker of regional cerebral synaptic SV2A density in rat lesion models of neurodegeneration. Healthy anesthetized rats had [11C]UCB-J PET and arterial blood sampling. We compared different models describing [11C]UCB-J brain uptake kinetics to determine its regional distribution. Blocking studies were performed with levetiracetam (LEV), an antiepileptic SV2A antagonist. Tracer binding was measured in rodent unilateral acute lesion models of Parkinsonism and Huntington’s disease, induced with 6-hydroxydopamine (6-OHDA) and quinolinic acid (QA), respectively. [3H]UCB-J autoradiography was performed in postmortem tissue. Rat brain showed high and fast [11C]UCB-J uptake and washout with up to 80% blockade by LEV. [11C]UCB-J PET showed a 6.2% decrease in ipsilateral striatal SV2A binding after 6-OHDA and 39.3% and 55.1% decreases after moderate and high dose QA confirmed by autoradiography. In conclusion, [11C]UCB-J PET provides a good in vivo marker of synaptic SV2A density which can potentially be followed longitudinally along with synaptic responses to putative neuroprotective agents in models of neurodegeneration.