新型骨显像剂99Tcm-ZL的制备和动物实验研究

以氯化亚锡为还原剂、用99Tcm标记唑来膦酸(ZL)制得99Tcm-ZL,研究了SnCl2·2H2O和ZL的用量以及溶液pH对标记率的影响,在pH=3-9、ZL的用量大于2mg和SnCl2·2H2O的用量大于40μg时,室温反应8min,可获放化纯和标记率大于90%的99Tcm-ZL,标记后6h内放化纯度保持不变.并对99Tcm-ZL的小鼠体内分布和兔显像进行了研究.小鼠体内生物分布表明,静脉注射后30min时,骨摄取达13.45%ID/g,am骨/肌和am骨/血分别达到28.01和16.96;兔显像表明,静脉注射75min后,即可获得清晰的骨显像.研究表明,99Tcm-ZL是一种稳定性好、制备简便、值得进一步深入研究的骨显像剂.     

Preparation and biodistribution of ^99Tc^m-PIDP as bone imaging agent

A novel zoledronic acid derivative,1-hydroxy-2-(2-propyl-1H-imidazol-1-yl)ethane-1,1-diyldiphosphonic acid (PIDP),was synthesized by three-step reactions from 2-propyl-1H-imidazole.It was labeled with 99Tcm in conditions of 0.1 mg SnCI2.2H2Cl2·2H2O at pH 6.0 and 99TcmO4-in aqueous solution for 20 min at room temperature.The labeling yield and radiochemical purity of 99Tcm-PIDP are both higher than 95%.The biodistribution results show that the bone uptake is up to 8.47%ID/g which is the maximum of bone uptake at 30 min after injection of 99Tcm-PIDP in mice.The pharmacokinetic parameters can be estimated from the exponential equation of C=59.565e-11.307t+ 2.069e-1.211t.The clear bone image of rabbit was obtained at 120 min after injection of 99Tcm-PIDP.The results indicate that 99Tcm-PIDP has highly selective uptake in the skeletal and low uptake,rapid clearance in soft tissues,so it would be a potential novel bone imaging agent.     

Preparation and preliminary biological evaluation of 99mTc-ANMdU

Technetium-99m-labeled-5-{2-sulfanylethyl-[2-(2-sulfanylethylamino)acetyl]amino}-methyl-2′-deoxy- uridine (99mTc-ANMdU) was reported. The precursor ANMdU was synthesized by six-step reactions and all intermediates were verified with MS and 1HNMR. Using SnCl2 as reducing agent, a labeling reaction was carried out at 100°C for 30 min. The radiochemical purity of the 99mTc-ANMdU was 96.68%. Partition coefficients were 0.92 and 0.70 at pH 7.0 and 7.4 of the phosphate buffer saline, respectively. Biodistribution of 99mTc-ANMdU in normal mice showed that the initial uptake of 99mTc-ANMdU in vivo and the clearance was rapid.     

肾显像剂 ~(99m)Tc-Diol 的制备及其基础实验

报道了肾显像剂９９ｍＴｃ－１，２－二羟基丙基磷酸（Ｄｉｏｌ）的制备方法及其动物实验研究。结果显示，９９ｍＴｃ－Ｄｉｏｌ注入小鼠体内５ｍｉｎ后在肾脏达最大摄取率（３４．０６±４．６７％ＩＤ／ｇ）；注入家兔５ｍｉｎ后双肾动态显像最清晰。表明９９ｍＴｃ－Ｄｉｏｌ是一种肾脏摄取率高、摄取速度快的新型肾显像剂。     

多巴胺D2受体显像剂99Tcm-m-Br-p-EBZM的合成

以与多巴胺有较高亲和力的2-溴-4-(1-乙基-吡咯烷基-2-甲基)-氨甲酰基-5-甲氧基-苯胺为母体进行结构改造,再与L,L-乙撑基胱氨酸二聚物(L,L-ethylenecysteine dimer,ECD)分子偶联合成了标记前体m-Br-p-EBZM,再通过两步法进行99Tcm标记,制备99Tcm-m-Br-p-EBZM,并对其进行了稳定性的考察.结果成功制备了99Tcm-m-Br-p-EBZM,放化纯度＞98%,且有较好的稳定性和较高的脂溶性.表明99Tcm-m-Br-p-EBZM可能成为理想的多巴胺受体显像剂.     

Preparation of ^99mTc-PQQE and preliminary biological evaluation for the NMDA receptor

The 4,5-dioxo-4,5-dihydro-1H-pyrrolo(2,3-f)quinoline-2,7,9-tricarboxylic acid 2-ethyl ester 7,9-dimethyl ester (PQQE) was synthesized on the basis of Pyrroloquinoline quinine (PQQ). 99m Tc-PQQE was prepared using stannous fluoride (SnF 2 ) as reducing agent. Biological characteristics of 99m Tc-PQQE include lipophilic and the charge properties were compared to 99m Tc-PQQ. The biodistributions of 99m Tc-PQQE in mice and brain regional distribution were performed. In vivo distribution of 99m Tc-PQQE in mice indicates that the concentration ratio of drug and blood increases steadily over time. The major radioactivity may be metabolized by the hepatic and renal system. The elimination-phase half-time (t1/2β) results indicate that the residence time of 99m Tc-PQQE (203.92) in the body is twice as long as 99m Tc-PQQ (100.45). The uptake of 99m Tc-PQQE in brain was improved due to the ameliorating of charge and lipophilicity. The highest total regional brain uptake of 99m Tc-PQQE was in the frontal lobe and hippocampus, where the NMDA receptor is very abundant. 99m Tc-PQQE had a good target to nontarget ratio (hippocampus/cerebellum) which preserved a higher value (peak 4.0 at 120 min) from 60 min to 180 min after injection. In vitro autoradiographic results are in close agreement with the regional brain map. The enrichment can be blocked by N-methyl-D-aspartate receptor (NMDAR) redox modulatory site antagonists-ebselen (EB). This work suggests that 99m Tc-PQQE has some specific targeting to the NMDA receptor.     

心肌显像剂锝-99m-胺苯缩硫脲的合成及其初步动物实验

3-(对三甲氨乙基)-苯丙烷-2,3-二酮-双(N-甲基缩氨基硫脲)-碘化物(p-TPA-DTS)是由氨乙基苯为原料,通过甲基化、丙酰化、亚硝基化和与甲缩氨基硫脲缩合及季铵化合成的。该化合物在pH3的水溶液中,由氯化亚锡还原高锝酸钠制备而得狸-99m-胺苯缩硫脲,本品用兔实验显示清晰的心肌显像,并能迅速经肝脏细胞运行。     

肝ASGP受体功能显像剂的制备及显像研究

采用ＦＰＬＣ快速纯化人血清白蛋白,利用双功能试剂２－亚胺基－２－甲氧基乙基－１－硫代－半乳糖甙与伯胺基的成脒反应,将工半乳糖残基引入人血清白蛋白分子,得到平均糖密度为３０的新半乳糖人血清白蛋白（ＮＧＡ）;用直接法制备＾９９ｍＴｃ－ＮＧＡ,其放化纯大于９０％,且室温下可稳定６ｈ以上,符合显像要求。＾９９ｍＴｃ－ＮＧＡ小鼠体内分布实验及大鼠、兔和狗的显像研究均表明＾９９ｍＴｃ－ＮＧＡ能够被肝脏特异摄取     

~(99m)Tc-帕米膦酸盐的制备及骨分布

为观察99mTc标记的帕米膦酸盐(Pamidronate,PAM)的骨分布特点,以氯化亚锡为还原剂,优化99mTc直接标记PAM的条件,研究SnCl2(Ⅱ)含量、配体用量、pH及反应时间对标记率的影响,确定了优化的标记条件;考察99mTc-PAM的体外稳定性;评价99mTc-PAM在正常鼠体内的生物分布,尤其是骨摄取情况,比较99mTc-PAM与99mTc-MDP在正常小鼠体内的骨摄取。实验结果表明,PAM的99mTc标记方法简单,标记率大于95%,标记物体外稳定性好。正常鼠体内分布实验发现,99mTc-PAM骨摄取很高,且滞留时间长,在血液中清除快,在体内主要通过肾代谢;正常大鼠SPECT显像骨组织清晰可见,具有很好骨显像效果。与99mTc-MDP在正常小鼠体内的生物分布结果比较表明,99mTc-PAM的骨放射性摄取及骨与血放射性摄取比在不同时相均优于99mTc-MDP。研究表明,99mTc-PAM具有理想的骨显像性能,可用于骨显像、骨损伤探测以及肿瘤骨转移检测等应用研究。     

Biodistribution and pharmacokinetics of ^99mTc—CQDO and ^99mTc—CQDO—MeB for new myocardial imaging agent

A comparison of ~(99m)Tc- CQDO and ~(99m)Tc-CQDO-MeB has been made for biodistribution and pharmacokinetics. ~(99m)Tc-CQDO and its adducts of methaneboronic acid ~(99m)Tc-CQDO-MeB were prepared by the reduction of Na~(99m)TcO_4 with SnCl_2·2H_2O in aqueous solution. Radiochemical purity of ~(99m)Tc-CQDO and ~(99m)Tc-CQDO-MeB determined by TLC were over 95% after extraction. Biodistributions of ~(99m)Tc-CQDO and ~(99m)Tc-CQDO-MeB in mice demonstrated that both of them could be easily absorbed by myocardium, and the peak uptake of each were 10.83±2.2% ID/g and 11.84±1.69%ID/g, respectively. ~(99m)Tc-CQDO showed rapid clearance from myocardial tissue while ~(99m)Tc-CQDO-MeB had long retention in heart muscle. The myocardial uptake of ~(99m)Tc-CQDO was only 5.88±1.66%ID/g at 10 min. and the uptake of ~(99m)Tc-CQDO-MeB was 7.42±0.17%ID/g at 60 min. The elimination of each from blood has a biexponential pattern, the first T_(1/2) is 1.38 and 1.5 min, respectively. The partition coefficient of ~(99m)Tc-CQD     

新的脑灌注显像剂^99mTc—MRP20配体的合成与标记

报道了Ｎ－［２（１Ｈ吡咯基甲基）］Ｎ＇－（４－戊烯－３－酮－２）－１，２－乙二胺（ＭＲＰ２０）的光谱数据与结构相符；元素分析结果与理论值一致；ＭＲＰ２０在室温下用亚锡还原可与＾９９ＴｃＯ（Ⅲ）生成配合物，标记率和放化纯大于９０％。     

新型肾功能显像剂^99mTc—MAG3的合成及动物实验

由三甘氨肽与氯乙酰氯、苯甲硫羟酸反应得到^99mTc-MAG3的前体化合物BZ－MAG3，并用^99mTc标记，即得^99mTc-MAG3，标记率达97％。经动物实验表明：^99mTc-MAG3能以原形快速经肾排泄。     

多巴胺D2受体显像剂99Tcm-mEBZM生物学评价

将ECD(L,L-ethyl cysteinate dimer)分子与对多巴胺D2受体具有较高亲和力的苯酰胺分子(BZM)偶联,制备99Tcm-mEBZM,并研究了99Tcm-mEBZM在大鼠和小鼠体内的生物分布.结果显示,99Tcm-mEBZM具有较高的体外稳定性和较高的脂溶性,在小鼠的生物分布中呈现较高的进脑量(2 min时为2.97%ID@g-1),小鼠与大鼠的纹状体/小脑比值可达到1.55,提示标记物与纹状体的结合具有特异性.     

受体显像剂~(99m)Tc-NCAM在小鼠脑组织中的药物代谢动力学研究

对N-甲基-D-天冬氨酸(NMDA)受体拮抗剂锝标记N-[2-(N-(2-巯基乙基))氨基乙酰基]-N-(2-巯基乙基)-3,5-二甲基金刚烷胺基乙酰胺(99mTc-NCAM)进行小鼠脑组织中药物动力学研究。KM小鼠尾静脉注射0.2mL(7.4MBq)99mTc-NCAM,分别于注射后5、10、30、60、120、180min处死,取大脑皮层、纹状体、海马、小脑和丘脑,称重和测计数。以相同的时间点,小鼠断尾取血20μL,测计数。用药物动力学定域模型进行脑组织和血药动力学研究。结果表明,99mTc-NCAM静脉注射给药后迅速进脑,在大脑皮层和海马有较高的摄取,最高摄取分别为1.51±0.13%ID/g和0.74±0.002%ID/g。理论计算表明,99mTc-NCAM在小鼠体内符合二室模型,并获得各种脑组织和血液的药物动力学方程和参数。99mTc-NCAM能透过血脑屏障进入小鼠脑内特定区域,以NMDA受体分布最多的大脑皮层和海马摄取较多,可望成为一种新的NMDA受体显像剂,用于一些神经退行性疾病的诊断预后等。     

二膦酸类骨显像剂的研究

研究了１,２－二羟基－１,２－二膦酸乙烷（ＤＨＰＥ）、２,３－二羟基－２,３－二膦酸丁烷（ＤＨＰＢ）及２,４－二羟基－２,４－二膦酸戊烷（ＤＨＰＰ）三种络合物的合成并用＾９９ｍＴｃ标记,研究了影响记率的因素和标记的电佳方法。对这三种络合物进行了小鼠体内生物分布的对比研究,结果表明３种化合物与＾９９ｍＴｃ均能很好地络合,并具有亲骨性。     

~(99m)锝-特丁基异腈心肌显像药盒的研制及初步临床应用

~(99m)锝-特丁基异腈(~(99m)Tc-TBI)是第一个较成功地进入临床试用阶段的~(99m)锝标记心肌显像剂。~(99m)Tc-TBI可用还原法或配体交换法标记。本文采用自制的TBI与改进的配体交换法药盒,检测15例,进行静息与运动试验时的平面与断层显像,并与~(201)Tl心肌显像对照,以探讨~(99m)Tc-TBI临床应用的特点。     

心肌显像剂99mTcN-BMPBDA的制备及动物体内分布研究

为了寻找新的具有亲心肌性质的＾９９ｍＴｃＮ药物,合成了一种新的Ｎ２Ｓ２配体：Ｎ,Ｎ＇－二（２－巯基丙基）－１,２－苯二胺（ＢＭＰＢＤＡ）。以ＳｎＣｌ２为还原剂,Ｈ２ＮＮＨ－（Ｃ＝Ｓ）－ＳＣＨ３为Ｎ＾３－给予体,通过交换反应制备了放化纯大于９０％的＾９９ｍＴｃＮ－ＢＭＰＢＤＡ。探讨了ｐＨ值对＾９９ｍＴｃＮ－ＢＭＰＢＤＡ放化纯的影响,并对其小鼠生物分布进行了研究。结果表明,＾９９ｍＴｃＮ－ＢＭＰＢＤＡ     

99Tcm-CLP肺肿瘤显像探针的制备

从牛鼻软骨中获取HA-CLP复合物,4mol/L盐酸胍解离和亲和层析法纯化CLP.然后用SnCl2活化CLP后进行99Tcm离子螯合标记,获得了肺肿瘤显像探针99Tcm-CLP.结果显示99Tcm-CLP的标记率和放射化学纯度均达到90%以上,体外与HA的亲和力KA为1.12×109 L/mol,将99Tcm-CLP注入肺腺癌裸鼠体内发现在瘤区与HA有较好的浓集.表明99Tcm-CLP标记探针可用于肺肿瘤的显像研究.