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

目的：研究脑乙酰胆碱酯酶（AChE）活性的正电子断层扫描（PET）诊断显像剂[^11C]4-乙酰氧基-N-甲基哌啶（[^11C]MP4A）在大鼠体内的摄取和分布。方法：正常雌性SD大鼠尾静脉注射[^11C]MP4A，按注射后5、15、25、35、45和60min时间点分组后断头处死动物，迅速取血，分离脏器和脑（大脑皮质、小脑和脑干），用自动γ放射性计数仪计算经衰变校正后不同时间点各脏器放射性摄取率，以％ID／g表示。结果：一次剂量的[^11C]MP4A静脉注射后，血中5min时％ID／g为（13．44±1．88），清除迅速，60min时接近于基线水平；各脏器组织中％ID／g 15-25min达到稳态；大脑皮质5min％ID／g为（2．26±0．29）。脑内各区域的摄取在注射后15～25min达到稳态。皮质的平均％ID/g〉小脑，两者比值范围为1．13～2．08；60min时小脑、脑干和皮质的％ID／g与其最高峰相比分别下降了77％、80％和40％；皮质放射活性清除最慢。结论：[^11C]MP4A血中清除迅速。脑各区域摄取在短时达到稳态，提示[^11C]MP4A有较好的脂溶性，易透过血脑屏障；皮质摄取比小脑高但清除慢，表明[^11C]MP4A能更好反映皮质AChE活性，适合作为脑AChE活性的PET诊断显像剂。     

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.     

在变性病性痴呆中11C-MP4A PET显像

阿尔茨海默病(AD)的病情发展和中枢乙酰胆碱酯酶(AChE)活性下降密切相关.利用乙酰胆碱类似物11C-MP4A PET显像,检测脑内AChE活性,可以帮助老年性痴呆的早期诊断、鉴别诊断和病情的随访.     

不同类型痴呆脑代谢改变图型:~(18)F-FDG PET显像

目的探讨不同类型痴呆患者基于像素水平的脑代谢图型特点。方法对最终临床诊断为阿尔茨海默病(20例)、额颞叶痴呆(20例)、路易体痴呆(10例)、进行性核上性麻痹(7例)、原发性进行性失语(3例)、皮质基底节变性(1例)和多系统萎缩(1例)等认知功能障碍患者的18F-FDG PET显像资料进行回顾分析,描述各种神经变性疾病脑代谢降低区域和程度。结果 SPM分析表明,各种神经变性疾病引起的痴呆18F-FDG PET显像均表现为皮质代谢降低,但其代谢图型变化明显不同:阿尔茨海默病组以双侧颞顶叶和额叶皮质代谢降低为主,基本感觉运动皮质、枕叶、基底节和丘脑活性保留;额颞叶痴呆组额叶和颞叶皮质不对称性代谢降低,伴部分顶叶皮质和基底节、丘脑等皮质下核团不同程度代谢降低;路易体痴呆组枕叶、视皮质和双侧颞上回前部代谢降低;进行性核上性麻痹组双侧前额叶背外侧、颞叶前外侧、中脑和双侧尾状核代谢降低;原发性进行性失语组左侧额叶Broca区、左侧颞叶皮质(除左侧颞上回后部)和右侧颞叶内侧皮质代谢降低;皮质基底节变性组双侧中央沟周围额顶叶皮质(右侧显著)、右侧基底节代谢降低;多系统萎缩组双侧小脑背外侧皮质和左侧壳核代谢降低。结论神经变性疾病所致痴呆在18F-FDG PET显像中表现出各自特征性脑代谢降低图型,18F-FDG PET显像有可能成为痴呆鉴别诊断的一种辅助手段。     

[^11C]-β-CFT脑多巴胺转运体PET显像在帕金森病诊断中的应用

目的:探讨[11C]-β-CFT多巴胺转运体(DAT)PET显像在帕金森病(PD)早期诊断及病情严重度评估的应用价值.方法:对早期PD组,晚期PD组和正常对照组进行[11C]-β-CFT基底节区DAT PET显像,比较3组间基底节DAT摄取指数差异,分析PD组基底节区DAT摄取指数与UPDRS评分的相关性.结果:PD患者基底节区DAT摄取指数显著降低;其中单侧PD患者症状/同侧基底节区DAT摄取指数明显低于对照组.PD组基底节各亚区DAT摄取指数与UPDRS运动评分呈显著负相关.结论:[11C]-β-CFT基底节DAT PET显像有助于PD的早期诊断及病情严重度的评估.     

~(18)F-FDG PET显像鉴别阿尔茨海默病与额颞叶痴呆临床价值

目的探讨18F-FDG PET显像在阿尔茨海默病与额颞叶痴呆鉴别诊断中的应用价值。方法对临床明确诊断的阿尔茨海默病(20例)和行为异常型额颞叶痴呆(20例)患者的18F-FDG PET显像资料进行回顾,分析两组患者皮质代谢降低脑区间的差异。结果视觉分析显示,两组患者均表现为皮质代谢降低,阿尔茨海默病患者以双侧颞顶叶和后扣带回代谢降低明显,以及部分额叶皮质代谢降低,而基底节和丘脑不受累,18/20患者双侧大脑半球皮质代谢降低范围和程度基本对称;额颞叶痴呆患者额叶和前颞叶皮质代谢均降低,其中11例同时伴部分顶叶皮质和基底节、丘脑等皮质下核团不同程度降低,16/20患者双侧大脑半球代谢降低程度和范围明显不对称,4例以右侧为主、12例以左侧为主。结论由于18F-FDG PET显像所显示的阿尔茨海默病和额颞叶痴呆患者之皮质代谢降低图型不同,故具有较好的鉴别诊断价值。     

~(11)C-PIBPET和~(18)F-FDGPET显像诊断阿尔茨海默病与遗忘型轻度认知损害的临床价值

目的应用11C-PIB PET和18F-FDG PET显像研究阿尔茨海默病和遗忘型轻度认知损害患者β-淀粉样蛋白(Aβ)沉积与葡萄糖代谢之间的关系,联合载脂蛋白E(ApoE)基因型进一步探讨遗忘型轻度认知损害与阿尔茨海默病的相关性。方法利用PET显像对阿尔茨海默病(14例)、遗忘型轻度认知损害(10例)和正常对照者(5例)脑组织Aβ沉积和葡萄糖代谢变化进行分析,采用聚合酶链反应-限制性片段长度多态性方法对ApoE基因型进行分析。结果阿尔茨海默病组患者11C-PIB标准化摄取比值在下顶叶、颞叶外侧、额叶、后扣带回皮质和楔前叶、枕叶和纹状体均高于正常对照组(P0.05);遗忘型轻度认知损害组患者脑组织11C-PIB结合水平呈双峰形。11C-PIB+aMCI亚组与阿尔茨海默病组、11C-PIB-aMCI亚组与正常对照组之间11C-PIB标准化摄取比值差异均无统计学意义(P0.05)。18F-FDG PET显像显示,3/5例11C-PIB+aMCI亚组患者双侧顶叶、颞叶和楔前叶代谢减低,其中2例ApoEε4等位基因携带者随访期间进展至阿尔茨海默病;3/5例11C-PIB-aMCI亚组患者双侧额叶和前扣带回代谢减低。结论11C-PIB PET显像是筛查具有阿尔茨海默病病理特点的遗忘型轻度认知损害患者的有效工具。具有阿尔茨海默病病理特征的遗忘型轻度认知损害患者可伴有顶叶、颞叶外侧皮质和楔前叶代谢减低,其中ApoEε4等位基因携带者更易进展至阿尔茨海默病痴呆。     

~(11)C-CFT PET显像评价帕金森病与多系统萎缩P型患者脑内多巴胺转运体分布特点的研究

目的基于~(11)C-CFT正电子发射计算机断层(PET)显像评价帕金森病(PD)与多系统萎缩P型(MSA-P)患者脑内多巴胺转运体(DAT)分布特点,评估~(11)C-CFT PET显像在PD与MSA-P鉴别诊断中的价值。方法回顾性分析年龄、性别和疾病严重程度匹配的32例MSA-P患者(MSA-P组)和56例PD患者(PD组)的临床资料以及~(11)C-CFT PET影像资料;另选择年龄匹配的健康对照者20例为对照组。应用感兴趣区技术获得3组研究对象的尾状核、前壳核和后壳核的DAT分布半定量值,对各感兴趣区的DAT分布半定量值、相互比值和不对称性进行对比研究。建立受试者工作特征曲线(ROL),利用曲线下面积评估基于~(11)C-CFT PET显像所得相关参数对PD和MSA-P的鉴别能力。结果与PD组比较,MSA-P组患者病程更短、进展速度更快(P0.000 1)。与对照组比较,PD组和MSA-P组尾状核、前壳核和后壳核的DAT分布半定量值均显著减低(P0.000 1),且后壳核降低最为显著。PD组和MSA-P组尾状核、前壳核和后壳核的DAT分布半定量值及其不对称指数比较均差异无显著性。PD组和MSA-P组纹状体各感兴趣区DAT分布半定量值中,前壳核/尾状核比值(AP/C)、后壳核/前壳核比值(PP/AP)均差异无显著性;但MSA-P组后壳核/尾状核比值(PP/C)PD组(P0.05),两组PP/C比值的ROL曲线下面积为0.696(P=0.002);以0.611作为PP/C比值的临界值,其对MSA-P和PD鉴别诊断的灵敏度和特异度分别为71.9%和62.5%。结论 ~(11)C-CFT PET显像可以精准显示MSA-P及PD患者脑内多巴胺能神经元的突触前功能损害,但尚不能有效鉴别两种疾病。     

[~(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。     

Imaging of activated microglia with PET and [11C]PK 11195 in corticobasal degeneration.

Positron emission tomography (PET) using [(11)C]PK 11195, a ligand for peripheral benzodiazepine receptor binding sites, offers the opportunity to image activated microglia in vivo. This tool may therefore be used to display the occurrence of microglial activation in the course of neurodegeneration. A patient with the clinical diagnosis of corticobasal degeneration (CBD) and left-sided symptoms was studied using fluorodeoxyglucose (FDG) and [(11)C]PK 11195 PET. We found a marked right hemispheric hypometabolism and asymmetric microglial activation in corresponding areas of the basal ganglia and right temporal and parietal cortex. [(11)C]PK 11195 PET suggests involvement of microglial activation in the pathogenesis of CBD.     

Development of novel PET probe [11C](R,R)HAPT and its stereoisomer [11C](S,S)HAPT for vesicular acetylcholine transporter imaging: A PET study in conscious monkey

Carbon‐11‐labeled (R,R)trans‐8‐methyl‐2‐hydroxy‐3‐[4‐[2‐aminophenyl]piperizinyl]‐tetralin ([¹¹C](R,R)HAPT) and its stereoisomer [¹¹C](S,S)HAPT were developed for imaging vesicular acetylcholine transporters (VAChTs), exclusively located in presynaptic cholinergic neurons. Both positron emission tomography (PET) probes were evaluated in the brain of conscious monkey (Macaca mulatta) using high‐resolution PET. Time‐activity curves (TACs) of [¹¹C](R,R)HAPT peaked within 5 min after the injection in all regions except the caudate and putamen, both of which showed peaks around 20 min postinjection. The regional distribution patterns of [¹¹C](R,R)HAPT determined as total distribution volume (V_t) were highest in the putamen, high in the caudate, intermediate in the amygdala, hippocampus, and thalamus, lower in the cingulate gyrus and frontal, temporal, and occipital cortices, and lowest in the cerebellum. In contrast, the distribution and TACs of [¹¹C](S,S)HAPT were homogeneous in all regions. The uptake of [¹¹C](R,R)HAPT was reduced by 1 mg/kg (?)‐vesamicol, a specific VAChT antagonist, in all regions except the cerebellum, but not by 0.1 mg/kg SA4503, a specific sigma‐1 receptor agonist. These results well reflect the in vitro affinity assessments using rat cerebral membranes. They also demonstrate that [¹¹C](R,R)HAPT is a potential PET probe for noninvasive and quantitative imaging of VAChT in the living brain. Synapse 68:283–292, 2014 . © 2014 Wiley Periodicals, Inc.     

Brain uptake and plasma metabolism of [11C]vinpocetine: a preliminary PET study in a cynomolgus monkey.

Vinpocetine, a vinca alkaloid, is a widely used therapeutic agent in patients with acute and chronic stroke. To reveal the mechanisms of vinpocetine action in the brain, vinpocetine was labeled with 11C. Positron emission tomography (PET) was used to determine the uptake and distribution of [11C]vinpocetine in brain regions and the trunk of a cynomolgous monkey in two independent measurements. The concentration of vinpocetine and its labeled metabolites was determined in blood and plasma using high-performance liquid chromatography (HPLC). Almost identical measurements were obtained in the two independent studies. After intravenous administration, following an initial peak, the total concentration of radioactivity in blood was relatively stable with time, whereas the concentration of the unchanged compound decreased with time in an exponential manner. The uptake of [11C]vinpocetine in brain was rapid, and 5% of the radioactivity totally injected was present in the brain 2 minutes after drug administration, indicating that the compound entered the brain readily. The radioactivity uptake was heterogeneously distributed among brain regions and was highest in the thalamus, the basal ganglia, and certain neocortical regions. The high brain uptake and the heterogeneous regional distribution indicate that direct central nervous system (CNS) effects of vinpocetine must be considered as explanation for the therapeutic effects. The detailed exploration of this suggestion requires further studies.     

In vitro and in vivo characterization of (+)-3-[11C]cyano-dizocilpine

Summary. (+)-3-[¹¹C]Cyano-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine ([¹¹C]MKC) was successfully synthesized as a potential radiotracer for PET studies on the NMDA receptor channel complex. In vitro binding properties of [¹¹C]MKC were investigated with newly developed techniques for efficient evaluation of ¹¹C-labeled compounds. The association curve of [¹¹C]MKC binding in rat forebrain membranes showed that the specific binding reached an equilibrium within 30 min. Specific binding was saturable with affinity constant K_D = 8.2 ± 0.4 nM and B_max = 1.62 ± 0.04 pmol/mg protein with glutamate and glycine included in the incubation medium. The binding of [¹¹C]MKC was decreased by extensive washing of the membrane preparation. (+)- and (−)-Dizocilpine, 3-cyano-dizocilpine, and ketamine inhibited the specific binding of [¹¹C]MKC with IC₅₀ values of 37.3, 445.0, 65.8 nM and 3.91 μM, respectively. High specific binding in in vitro autoradiography was distributed predominantly in telencephalic regions (the hippocampus, cerebral cortex, and striatum) followed by thalamus. PET studies using rhesus monkeys under anesthesia showed high uptake of [¹¹C]MKC in the temporoparietal and frontal cerebral cortices, striatum, and thalamic regions, although it is problematic to verify the specific binding in vivo by PET. Accepted January 5, 1998; received October 7, 1997     

Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET

Parenterally administered D-amphetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D-amphetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D-amphetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D-amphetamine administration (n = 5); at baseline, 2 and 6 h postdrug (n = 4); or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D-amphetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D-amphetamine concentrations. In conclusion, orally administered D-amphetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.     

11C]-NS 4194 versus [11C]-DASB for PET imaging of serotonin transporters in living porcine brain

In vitro, the novel diazabicyclononane NS 4194 has several thousand-fold selectivity for blocking the transport into rat brain synaptosomes of [(3)H]-serotonin in comparison to [(3)H]-dopamine or [(3)H]-noradrenaline. We have prepared [(11)C]-NS 4194 in order to test its properties for PET imaging of brain serotonin transporters in comparison with the well-documented tracer [(11)C]-DASB. Both compounds had rapid clearance from blood to brain of living pigs. The apparent equilibrium distribution volumes in cerebellum were 35 ml g(-1) for [(11)C]-NS 4194 and 11 ml g(-1) for [(11)C]-DASB. Pretreatment of pigs with citalopram did not reduce the uptake of either tracer in cerebellum, validating the use of that tissue as a nonbinding reference tissue for kinetic analysis of specific binding. The binding potential (pB) calculated for [(11)C]-NS 4194 using arterial input models was close to 0.5 in the telencephalon, and was 60% displaced by citalopram. However, the reference tissue method of Lammertsma was unsuited to calculate pB for this tracer, apparently due to its excessive nonspecific binding. In contrast to the relatively homogeneous binding of [(11)C]-NS 4194, the pB of [(11)C]-DASB ranged from 0.6 in frontal cortex to 2 in the mesencephalon when calculated by the method of Lammertsma. Parametric maps of the pB of [(11)C]-DASB showed a pattern consistent with the known distribution of serotonin transporters in pig brain in vitro, and there was a uniform displacement of 80% of the specific binding after citalopram treatment in vivo. In conclusion, [(11)C]-DASB is in several respects superior to [(11)C]-NS 4194 for the detection of serotonin uptake sites by PET.