新型肺癌小分子多肽的~(131)I标记及其在小鼠体内的生物分布

建立肺癌特异性靶向小分子多肽cNGQGEQc的~(131)I标记方法,研究~(131)I-cNGQGEQc在正常小鼠体内的生物学分布特性。采用氯胺-T法对N端连接有酪氨酸的cNGQGEQc进行~(131)I标记,测定~(131)IcNGQGEQc的标记率、放化纯度、脂水分配系数及在生理盐水(NS)和正常人血清中的体外稳定性,并对标记物在正常小鼠体内的分布进行了初步研究。结果表明,~(131)I-cNGQGEQc的标记率大于90%,比活度为0.4TBq/g;~(131)I-cNGQGEQc在正常人血清和NS中较稳定;~(131)I-cNGQGEQc的脂水分配系数lgP为—1.68,体内生物分布结果表明,肾脏的放射性摄取率在1 h和12 h分别为(10.59±4.66)%ID/g和(1.79±0.89)%ID/g,肾脏的放射性摄取明显高于其他脏器,表明~(131)I-cNGQGEQc主要经肾脏代谢。以上结果表明,~(131)IcNGQGEQc的标记率较高,在体外具有良好的稳定性。~(131)I-cNGQGEQc为水溶性,可用于进一步的靶向诊断与治疗的研究。     

~(131)I标记新型小分子肽VP2

本文通过双功能偶联剂5-(三正丁基锡)-3-吡啶甲酸-N-琥珀酰亚胺酯(SPC)将131I标记到小分子融合多肽VP2上,研究了131I标记多肽VP2的体内外稳定性及在正常小鼠体内的代谢与分布。结果表明,该标记药物室温下放置48h后放化纯度仍可达97%,其在小鼠体内可通过胃肠道快速代谢,在甲状腺的摄取较低。用间接标记法得到的131I-SPC-VP2在体内外有良好的稳定性。     

~(67)Ga-EDTMP标记条件的研究及其在小鼠体内的生物分布

用加速器生产的∧67Ga制备了∧67Ga-EDTMP（乙二胺四甲撑膦酸）,研究了配位体用量、反应时间、反应温度和pH对标记率的影响,测定了标记物的体外稳定性及其在小鼠体内的生物分布。结果表明,标记率可达97%以上;∧67Ga-EDTMP有较高的骨吸收和T/NT值,并在72h内保持很高的水平。     

神经肽类似物DOTA-Substance P的~(177)Lu标记及其生物分布

为探讨神经肽类药物177 Lu-DOTA-Substance P(以下简称为177 Lu-DOTA-SP)用于人胰腺癌PANC-1的肿瘤显像及治疗的可能性,研究了DOTA-SP的177 Lu标记;考察了177 Lu-DOTA-SP在室温下生理盐水中与在37℃小牛血清中的稳定性;评价了177 Lu-DOTA-SP在正常昆明小鼠与人胰腺癌PANC-1模型裸鼠体内的生物分布特点,并对人胰腺癌PANC-1模型裸鼠进行了SPECT显像研究。结果表明,在优化条件下,DOTA-SP的177 Lu标记率90%,纯化后,177 Lu-DOTA-SP的放化纯度98%。177 Lu-DOTA-SP在生理盐水与5%小牛血清中显示了良好的稳定性,与浓度较高的血清(10%)竞争反应时,其降解稍快。177 Lu-DOTA-SP在正常昆明小白鼠体内的生物分布特点为:血清除快,肾放射性摄取高且滞留时间长;骨中有一定放射性摄取,且滞留长。177 Lu-DOTA-SP在人胰腺癌PANC-1模型裸鼠中的体内分布结果表明,肿瘤细胞中放射性摄取在给药后不同时间点均高于正常胰腺细胞中的放射性摄取,提示在PANC-1肿瘤细胞中有NK-1受体存在。SPECT显像结果显示,177 Lu-DOTA-SP在肿瘤细胞中放射性浓集并不明显。177 Lu-DOTA-SP应用于胰腺癌肿瘤显像与治疗的价值尚需进一步研究。     

含RGD序列多肽的~(188)Re标记及其生物分布

以fac-[188Re(CO)3(H2O)3]+为前体标记了含RGD的环状多肽H-c(RGDyK)(Pc1):75℃下反应30 min即可得到标记率和放化产率大于90%的目标产物188Re(CO)3-Pc1。此标记物在小牛血清及磷酸缓冲液(pH=7.4)中稳定性良好,Pc1对U87 MG细胞有良好的亲和力,半抑制常数(IC50)为84.9 nmol/L。生物分布数据显示,188Re-Pc1在血液内清除较快,且通过肝胆和肾代谢排出体外;在肿瘤内有一定的摄取。     

^131I标记肿瘤血管靶向多肽的实验研究

设计合成含精氨酸-精氨酸-亮氨酸（RRL）序列的多肽,并用氯胺-T法对其进行^131I标记,标记率约60％,放化纯度〉99％。体外放置24h放化纯度仍≥90％。肿瘤对^131I标记多肽的摄取在注射后明显高于其他器官,注药后24h,肿瘤对^131I-多肽的摄取约为0．65％ID／g,肿瘤与肌肉的放射性摄取比（T／NT）达9．08。以上结果表明：通过氯胺-T法对该多肽进行^131I标记是可行的,标记物可在体外稳定存放24h;^131I-多肽可以靶向肿瘤血管,有进一步研究的价值。     

3H11的~(123)I标记及其生物分布

采用Iodogen氧化法对胃癌单克隆抗体3 H11进行了123I标记,用PD-10层析柱分离纯化标记物,纸层析法测定标记物的标记率和放化纯度,评价标记物的体外稳定性,并观察了标记物在正常小鼠体内的生物分布。标记结果显示,123I-3 H11的优化标记条件为:Iodogen 10μg、3 H11 30μg、Na123I溶液20μL(13.3 MBq)、磷酸盐缓冲溶液100μL(pH7.4、0.2 mol/L)、常温下反应8 min,123I-3 H11标记率70%~80%;稳定性结果显示,标记物在4℃人血清中的体外稳定性较好,放置48 h后放化纯度92%;正常昆明鼠体内生物学分布显示,全抗3 H11血液半清除时间为12.25±0.25 h,胃组织有明显摄取。以上结果提示,123I-3 H11是一种很有前景的肿瘤放射免疫显像剂。     

~(99)Tc~mN-DMSA的制备及其生物分布

以SnCl2 ·2H2 O为还原剂 ,丁二酰二酰肼 (SDH)为N3 -离子提供体 ,在室温下制备 [99TcmN]2 + 中间体 ,然后与二巯丁二酸 (DMSA)发生配体交换反应 ,得到放射化学纯度大于 90 %的 99TcmN DMSA配合物。99TcmN DMSA在室温下 6h内稳定 ,脂水分配系数lgP =- 3.74 ,表明是一水溶性化合物。99TcmN DMSA在小鼠体内生物分布表明 ,与作为肾显像剂的99Tcm DMSA相比 ,其生物分布发生了较大的变化 ,99TcmN核的引入导致了较高的骨摄取值和较低的肾摄取值     

一种改进的99mTcN(NOEt)2的标记方法及其生物分布

为获得具有再分布特性的新型中性心肌灌注显像剂,采用了以ＳｎＣｌ２·２Ｈ２Ｏ为还原剂,ＳＤＨ为Ｎ＾３－离子提供体,在室温下制备了［＾ｍＴｃＮ］ｉｎｔ＾２＋中间体,然后与ＮＯＥｔ发生配体交换反应得到标记率〉９０％的＾９９ｍＴｃＮ（ＮＯＥｔ）２配合物。小鼠体内生物分布实验表明＾９９ｍＴｃＮ（ＮＯＥｔ）２具有较高的心肌摄取,在注射后５ｍｉｎ时心／血、心／肝、心／肺比值分别为１０．４８、２．０７、０．７４,     

NGR短肽的188Re标记及其在荷瘤裸鼠体内的生物分布和SPECT显像

采用¹⁸⁸Re标记含有天冬酰胺、甘氨酸、精氨酸（Asn-Gly-Arg,NGR）序列的肿瘤血管靶向性短肽,得到¹⁸⁸Re-NGR,观察了¹⁸⁸Re-NGR在荷HepG2肝癌细胞严重联合免疫缺陷（Severe Combined Immunodeficiency,SCID）裸鼠肿瘤模型中的生物分布,并对其进行了SPECT显像。结果显示,¹⁸⁸Re-NGR的标记率>85%,放化纯度>90%。¹⁸⁸Re-NGR在肿瘤模型鼠体内的生物分布显示,注射¹⁸⁸Re-NGR后12 h,肿瘤放射性摄取达最高,为(4.62±0.71)%ID/g,24 h时仍有(2.01±0.38)%ID/g,说明标记物在肿瘤内停留时间较长;竞争性抑制组中,12 h肿瘤放射性摄取为(1.43±0.61)%ID/g,明显低于实验组。肿瘤与肌肉组织的放射性摄取比(T/NT) 12 h为4.76。注射后1 h肿瘤可显像,4～8 h显像逐渐清晰,12 h时更为清晰。以上结果提示,¹⁸⁸Re-NGR具有良好的肿瘤血管靶向性。     

99Tcm标记糖肽及其在荷瘤小鼠体内的分布与代谢动力学

Glucose and galactose are conjugated to the N- mercaptoacetyl-Val-Gly-Gly (MAVGG). The glycopeptides and MAVGG are labeled with 99Tcm. The partition coefficients between octanol and water (Pow) are measured. Glycopeptides or MAVGG labeled with 99Tcm areinjected into the mice bearing S180 tumor. 10μL blood samples are withdrawn at different time points and the radioactivities are counted to calculate the effective halflife (T1/2) using a bi-exponential fit. Biodistribution is measured at 3 h postinjection and the percentage of injected dose per gram ( ID%/g ) and tumor to normal tissue ratio (T/NT) were calculated. The assigned structures were confirmed on the basis of IR, NMR and MS. The 99Tcm labeling yield 巨radiochemical purity is greater than 90%. The lgPow of 99Tcm-Glu-MAVGG, 99Tcm-Gal-MAVGG and 99Tcm-MAVGG are –1.974, –2.128 and –1.378, respectively. The T1/2αof the three labeled peptides are 24.3, 37.1, 46.3 min and T1/2β are 221.5, 158.4 and 198.4 min, respectively. The tumor uptakes at 3 h postinjection are 1.46, 1.55 and 0.67 for 99Tcm-Glu-MAVGG, 99Tcm-Gal-MAVGG and 99Tcm-MAVGG, respectively. Their T/NT for tumor over muscle are 3.74、7.38 and 3.53, respectively. The results demonstrated that after carbohydrate conjugate of peptides, the lipophilicity is decreased , the blood clearance is increased and the tumor uptake is enhanced. Of the two glucopeptides, 99Tcm-Gal-MAVGG shows faster blood clearance, higher tumor uptake and T/NT, which suggests the potential utility of 99Tcm-Gal-MAVGG as a suitable tumor imaging agent.     

99Tcm-MAG2-Ade肿瘤显像剂的合成及其生物活性研究

为了制备肿瘤显像剂^99Tc^m标记肽,合成并表征了新的碱基修饰的小肽配体9-[N-(S-三苯甲基巯基乙酰)二甘氨酰氨基乙基]腺嘌呤(Tr—MAG2-Ade)。通过直接标记法得到了水溶性配合物^99Tc^m-MAGz—Ade,并对其体外稳定性进行了检测。在荷瘤小鼠体内的生物分布结果表明,^99Tc^m-MAGz—Ade在肿瘤中有较高的摄取,肿瘤与肌肉的摄取比为5．7,肿瘤与血液的摄取比为1．55。血液清除较快,有望用于非腹部肿瘤的显像。     

不同电荷肿瘤乏氧显像剂的合成及生物分布

电荷是药物分子的重要性质,可以影响其在体内的生物学行为。为了研究不同电性质的肿瘤乏氧显像剂在体内的生物分布行为,合成了3种带有不同电荷的肿瘤乏氧显像剂(S)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酸甲酯(NI-Y-M)、(S)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酸(NI-Y)和(S)-N-(3-胺丙基)-3-(4-羟基苯基)-2-(3-(2-硝基咪唑基)丙酰胺基)丙酰胺(NI-Y-A),并进行了131I标记。3种化合物的标记率均大于95%,体外稳定性好。纸上电泳结果表明,在生理条件下,[131I]NI-Y-M为中性分子,[131I]NI-Y和[131I]NI-Y-A则分别呈现负电和正电的电性质。从荷S180肉瘤小鼠体内分布结果发现:3种标记物在肿瘤组织呈现出快摄取慢清除的趋势,并且在肿瘤中的放射性活度明显高于肌肉和心、脑、脾等组织;随着时间的延长,肿瘤的相对摄取率提高;4h时,动物肿瘤与肌肉、肿瘤与血液放射性摄取的比值数据显示,带正电荷的标记物[131I]NI-Y-A是最优的肿瘤乏氧显像剂。     

碘标记毒死蜱及其在小鼠体内的生物分布

为探讨¹³¹I标记毒死蜱（Chlorpyrifos, CPF）在小鼠体内的分布特点,采用Iodogen法对CPF进行¹³¹I标记,KM小鼠尾静脉注射¹³¹I-CPF（185 kBq/只,n=5）,分别于注射后5、10、30、60、120、240、1440 min取各脏器,计算每克组织摄取注射剂量的百分率（%ID/g）。结果显示,¹³¹I-CPF标记率达93.5%,放化纯度为96.9%,¹³¹I-CPF在小鼠体内广泛分布,主要经肺、胃、小肠、大肠、肌肉和颌下腺吸收,其放射性摄取率在注药后 10 min 时达高峰,分别为37.12%ID/g、6.18%ID/g、8.12%ID/g、8.15%ID/g、7.04%ID/g和7.02%ID/g;经肝和肾进行代谢,其放射性摄取率在5 min时分别为4.34%ID/g和8.50%ID/g, 4 h为0.22%ID/g和 0.69%ID/g。血液中放射性清除较快,放射性摄取率在注入后5 min时为37.27%ID/g,4 h为1.35%ID/g。碘标记CPF体外稳定,体内主要经肺和消化道吸收,肝、肾代谢,可用于进一步的微量示踪研究。     

Radioiodine-Labeling of Chlorpyrifos and Its Biodistribution in Mice

To investigate the preparation of radioiodinated Chlorpyrifos and its biodistribution in mice, Chlorpyrifos was labeled with¹³¹I using the Iodogen method. Biodistribution studies were carried out in KM mice. At different times after radiopharmaceutical i.v. administration (185 kBq¹³¹I-Chlorpyrifos/mouse, n=5), the animals were sacrificed. Blood samples and the tissues of interested were collected, weighted and counted. The percentage of injected does per gram (%ID/g) was calculated for each sample. The labeling yield of ¹³¹I-Chlorpyrifos was 93.5%, The radiochemical purity (RCP) was 96.9%. Biodistribution in mice demonstrated that¹³¹I-Chlorpyrifos was extensive, and the uptakes mainly occur in lung, stomach, small-intestine, colon, musle, and submaxillay gland, as indicated by their amount of 37.12%ID/g, 6.18%ID/g, 8.12%ID/g, 8.15%ID/g, 7.04%ID/g, and 7.02%ID/g at 10 min, respectively. And it was metabolized in liver and kidney, as indicated by their uptake of 4.34%ID/g and 8.50%ID/g at 5 min, and 0.22%ID/g and 0.69%ID/g at 4 h, respectively. In addition,¹³¹I-Chlorpyrifos was cleared out from blood quickly, and the uptake of¹³¹I-Chlorpyrifos in blood was 37.27%ID/g at 5 min, and decreased to 1.35%ID/g at 4 h post injection. In conclusion, ¹³¹I-Chlorpyrifos was stable in vitro and it was absorbed in lung and digestive tract, and it was metabolized mainly in liver and kidney, worthy of further investigation to trace the compound in vivo and in vitro.     

碘标白藜芦醇及其小鼠体内分布

通过碘¹³¹标记白藜芦醇探讨白藜芦醇在小鼠体内的分布代谢。采用过氧化物酶法对白藜芦醇进行¹³¹I标记;经乙酸乙酯萃取纯化,以聚酰胺薄膜为支持介质,V(三氯甲烷)∶V(丙酮)∶V(乙醇)∶V(水)=4∶4∶0.5∶0.4为展开剂,测定标记物的标记率和放化纯;KM小鼠尾静脉注射¹³¹I白藜芦醇（每只0.185MBq,n=5）。¹³¹I白藜芦醇标记率达69.3%,萃取分离后其放化纯为959%,3、7和15d后分别为92.0%、90.4%、90.1%;动物实验显示,¹³¹I白藜芦醇在小鼠体内广泛分布,主要经肝和肾进行代谢,5min时每克组织百分注射剂量率(%ID•g^-1)分别为16.35、13.05,在肠中也有较高分布,10min时%ID•g^-1为11.70;甲状腺的摄取率随时间的延长而增加。碘标白藜芦醇标记物较稳定,可用于进一步的微量示踪研究。     

Radioiodine-labeling of EGCG and Its Biodistribution in Mice

To establish the ¹²⁵I-EGCGlabeling method and investigate the biodistribution of ¹²⁵I-EGCG inmice, ¹²⁵I-EGCG was prepared by Iodogen solid labeling method, andwere isolated and purified by Sephadex-G25 agarose, The labeling yield andradiochemical purity of ¹²⁵I-EGCG was analyzed by polymide TLC. Thelabeling yield of ¹²⁵I-EGCG was 89.4% and its radiochemicalpurity(RCP) were 96.4%. The Biodistribution of ¹²⁵I-EGCG in mice wasmeasured at different times after caudal vein injection with 185 kBq for eachmice. The biodistribution in mice demonstrated that ¹²⁵I-EGCG wasdistributed into broad organs and tissuuues, especially in the Stomach, Smallintestine and Submaxillay gland, and the biggest uptake of ¹²⁵I-EGCGin there organs was 15.92、5.83and 11.56 %ID·g^-1respectively at 15 min post injection. In addition, ¹²⁵I-EGCG wascleared out from blood guickly, and theuptake of ¹³¹I-EGCG in blood was 11.95 at 5 min, anddecreased to 1.25 at 4 h post injection. Therefore, ¹²⁵I-EGCG wasstable and it was metabolized mainly in Stomach, Small intestine, Submaxillaygland, worthy of further investigation to trace the compound in vivo and invitro.     

188Re-NEMMPTDD的制备及生物分布研究

在合成新配体NEMMPTDD(2,2,9,9-四甲基-4,7-二氮-4-乙撑-(3,5-二甲基)哌啶-1,10-二硫癸烷)的基础上,以SnCl2作还原剂制备了8Re-NEMMPTDD。生物分布研究表明,该配合物的碘化油溶液具有较理想的肝摄取和滞留,非靶组织的摄取和滞留相对较低,配合物主要通过肾和胃肠代谢。