^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。     

放射性碘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)多肽序列,并用氯胺-T法进行131I标记,该标记方法131I标记率60%左右,标记物放化学纯度大于95%。体外放置24 h放化学纯度仍高于90%。动物体内分布研究结果显示,肿瘤对131I标记的RRL多肽的摄取在注射后明显高于对照肽。     

5-HTSUB>1A /SUB>受体显像剂S

为了找到适合123I标记的5-羟色胺(5-HT1A)受体显像剂,合成了4-三正丁基锡-N-[2-[1-(2-甲氧基苯基)]-1-哌嗪基]乙基-N-2-吡啶基-苯甲酰胺(MPPBu3Sn,标记前体),并采用双氧水标记法进行131I标记,得到标记物131I-MPPI,标记率大于90%,放化纯大于99%。初步动物实验结果显示,131I-MPPI在大鼠海马中摄取最多,30 min时,海马与小脑的摄取率比值为2.90,说明131I-MPPI浓集在海马中,与5-HT1A受体在脑中的分布一致;放射自显影结果显示,在注射8-OH-DPAT后,海马(CA3区)与小脑的光密度比值从13.98±0.87降至1.96±0.46,与阻断前差异显著,说明131I-MPPI与5-HT1A受体结合具有特异性;注射后5 min和120 min,甲状腺的摄取率分别为(0.069±0.020)%和(0.128±0.026)%,表明脱碘是其主要代谢途径;131I-MPPI对5-HT1A受体具有高度亲和性和特异性,可作为筛选其他化合物对5-HT1A受体亲和大小的工具药。     

125I标记紫杉醇的方法

摘要:采用改良的氯胺T法,先用稳定的NaI与紫杉醇作用,再以放射性Na125I标记紫杉醇(paclitaxel),建立了125I标记紫杉醇的方法。采用纸层析及HPLC测定标记产物的标记率、纯化后放射化学纯度,采用纸层析测定标记产物在不同温度、储存溶剂条件下的体外稳定性,红外光谱鉴定产物。改良Ch-T法所得标记产物的标记率与硝酸氧化法和传统氯胺T法相比较。结果显示,采用改良氯胺T法标记率约63.1%±5.7%,放射化学纯度约96.3%±1.3%;标记物储存于4℃生理盐水或乙醇储存体系中24h、120h,放化纯度分别＞95%和约90%;在血浆中稳定性也较好,在4℃ 、37℃放置24h,放化纯度分别为92.3%±0.4%、89.5%±0.6% 。以上结果表明,改良氯胺T法标记紫杉醇方法简便,标记率高,标记产物稳定性较好,能够满足放射性示踪实验的要求。     

23-羟基白桦酸的碘标记及其在荷肝癌HepA肿瘤鼠体内的分布

采用双氧水法对23-羟基白桦酸进行131I标记;以硅胶纸为支持介质,V=氧甲烷∶V甲醇=9∶1为展开剂,测定标记率及标记物放化纯;ICR小鼠和荷肝癌HepA肿瘤鼠尾静脉注射131I-23-羟基白桦酸(0.74 MBq/只)后考察标记物的药代动力学性质及荷瘤鼠体内分布.结果显示,131I-23-羟基白桦酸标记率达98%,其放化纯在1、4、8 d分别为98.5%、97.3%、95.8%.131I-23-羟基白桦酸在正常小鼠体内血液清除较快,其药代动力学模型符合二室模型.注射后0.5 h荷肝癌HepA肿瘤鼠肝摄取最高(9.14%ID·g-1组织),其次为肾、血、脾、肠、肺、肿瘤,脑中分布最少,仅为0.28%ID·g-1组织;肿瘤/肌肉比值＞3.表明碘标23-羟基白桦酸标记率高,标记物稳定;碘标记物在荷肝癌HepA肿瘤鼠中的肿瘤靶向摄取提高2倍,可能是一新型增效的核素靶向治疗药物.     

125I-RC-160的标记方法研究及其正常小鼠体内的分布特征

研究了一种高效碘标多肽RC - 16 0的方法 ,在其中以溴代琥珀酰亚胺 (NBS)为氧化剂 ,常规氯胺T法作为对照。对12 5I -RC - 16 0的标记率、比活度进行了评价 ,并观察12 5I -RC - 16 0在正常小鼠体内的生物分布特征。结果显示 :在丙酮:生理盐水 =1:1体系中 ,测得12 5I -RC - 16 0的标记率NBS法为 92 %,比活度为 1.95× 10 12 Bq/mmoL ,标记率随NBS用量增加而增高 ,最佳用量比为RC - 16 0 (μg):12 5I(MBq):NBS(μg) =3:7.4:1,且产物无需纯化 ;Ch -T法标记率为5 6 %,比活度为 0 .6 5× 10 12 Bq/mmoL ,经SepPaK -C18反向色谱柱纯化 ,12 5I -RC - 16 0的标记率可达 92 %。标记物在血中清除较快 ,注射后不到 1h血中的放射性就下降了 87.2 %;12 5I -RC -16 0在甲状腺及肾的浓集度很低 ,主要经过消化系统排出体外。     

125I标记人血白蛋白及其在家兔体内代谢的研究

采用氯胺-T法标记了3种不同来源的人血白蛋白。用预饱和的Sephadex G50柱分离纯化125I标记人血白蛋白,并用HPLC法对标记物进行分析鉴定。取分离后的125I标记白蛋白配制示 踪液,进行家兔体内代谢试验。用氯胺-T方法,125I标记人血白蛋白的标记率>80%。代谢研究表明,成都生物制品研究所柱层析、低温乙醇工艺和加拿大柱层析工艺生产 的人血白蛋白,其生物半减期分别为96.11±0.01、85.75±2.62和90.00±1.69,三者之间无显著性差异(P>0.05)。     

β-淀粉样蛋白斑块显像剂131 I-IMPY的合成与生物分布

为了找到合适的123I标记的脑内β淀粉样蛋白(A β)斑块的显像剂,根据文献资料,合成了2-(4′-二甲基氨基苯基)-6-三正丁基锡咪唑并[1,2-α]吡啶(IMPY),并采用双氧水标记法进行了131I标记,得到标记物131 I-IMPY,放射化学纯度大于95%.方法对合成原料和条件作了相应的改进,提高了合成的收率.正常小鼠体内分布试验表明,在注射131 I-IMPY后2 min和60 min,小鼠脑摄取率分别为(7.374±4.797)%/g和(0.967±0.409)%/g.说明131 I-IMPY在小鼠脑中初始摄取很高,清除很快.131 I-IMPY可能是一个很有发展潜力的A β斑块SPECT显像剂.     

靶向整合素α_vβ_3受体的新型RGDyC-PEG-PAMAM纳米探针的设计制备、~(131)I标记及其质量控制

本研究以具有优良生物学性能的聚酰胺-胺树状大分子(PAMAM)为纳米载体,将具有肿瘤靶向性的精氨酸-甘氨酸-天冬氨酸(RGD)与纳米载体相连,并通过放射性核素~(131)I进行标记,对标记物的体内外药效学性质进行评价,探讨将其应用于肿瘤特异显像和靶向治疗的可能性。从多肽化学修饰法角度设计精氨酸-甘氨酸-天冬氨酸-酪氨酸-半胱氨酸(RGDyC),利用点击化学法引入双功能基团PEG(NHS-PEG-MAL),采用"一锅两步"法制备RGDyC-PEG-PAMAM纳米复合物,通过核磁共振和紫外光谱进行表征确定产物,并检测纳米粒径分布和电位,用透射电镜(TEM)观察其形态大小及分布;进一步采用氯胺T法进行~(131)I标记,并测定标记率、标记物的稳定性及脂水分配系数。所设计的RGDyC-PEG-PAMAM纳米复合物制备产率为62.09%,~(131)I对其标记率为94.68%~98.87%,标记物在体外72h后放化纯大于80%,脂水分配系数lg P(正辛醇/水)为-1.59±0.09。所设计的RGDyC-PEG-PAMAM可采用氯胺T法成功完成~(131)I标记,制备与标记过程高效、简捷,标记物~(131)I-RGDyC-PEG-PAMAM具有良好稳定性和较高亲水性,成药性良好,为后期进一步考察体外肿瘤细胞摄取与生长抑制、评估人癌裸鼠异种移植瘤模型治疗及肿瘤显像等体内外药效学研究奠定了基础,~(131)I-RGDyC-PEG-PAMAM有可能作为一个新型SPECT探针应用于肿瘤特异显像与靶向治疗。     

β-淀粉样蛋白斑块显像剂~(131)I-IMPY的合成与生物分布

为了找到合适的123I标记的脑内β淀粉样蛋白(A β)斑块的显像剂,根据文献资料,合成了2-(4′-二甲基氨基苯基)-6-三正丁基锡咪唑并[1,2-α]吡啶(IMPY),并采用双氧水标记法进行了131I标记,得到标记物131 I-IMPY,放射化学纯度大于95%.方法对合成原料和条件作了相应的改进,提高了合成的收率.正常小鼠体内分布试验表明,在注射131 I-IMPY后2 min和60 min,小鼠脑摄取率分别为(7.374±4.797)%/g和(0.967±0.409)%/g.说明131 I-IMPY在小鼠脑中初始摄取很高,清除很快.131 I-IMPY可能是一个很有发展潜力的A β斑块SPECT显像剂.     

多巴胺D2受体显像剂Epidepride的合成及其^131I标记

以3－甲氧基水杨酸为原料合成了Epidepride[S-(-)-N-[1-乙基－2－吡咯烷基]-5－碘－2,3－二甲氧基基甲酰胺]及其标记前体（S－（－）－5－（三正丁基锡）－N（1－乙基－2－吡咯烷基）甲基]2,3-二甲氧基苯甲酸酰胺）,并采用双氧水法对标记前体进行^131I标记,获得了^131I-epidepride,标记率和放化纯度均大于95％。132I-epidepride溶液体外稳定性好,4℃放置15d放化纯度仍大于90％。^131I-epidepride与D2受体亲和力高,大鼠脑内纹状体与小脑的摄取比在320min时高达237;在脑内纹状体的吸收可被Spiperone安全阻断。因此,^131I－epideride有望成为多巴胺D2受体SPECT显像剂。     

Pharmacological studies of dopamine transporter imaging agent 125／131I－β－CIT

To prepare ^125/131I-β-CIT(2β-carbomethoxy-3β-(4-iodophenyl)tropane) as an imaging agent for dopamine transporter (DAT),the labeling method from tributylstannyl precursor with peracetic acid has been reported in this article.The radiochemical purity(RCP) of the labeled compound was over 95% determined by HPLC and TLC.The stability,partition coefficients were also determined.The pharmacological studies of the imaging agent were performed in rats,mice,rabbits and normal monkey.The ligand showed preferable uptake in rats,mice,rabbits and normal monkey.The ligand showed preferable uptake in brain (1.9%ID/organ in rats and 4.5%ID/organ in mice at 5min).The ratios of striatum/cerebellum,hippocampus/cerebellum and cortex/cerebellum were 29.8,3.97and 4.75 at 6h in rats,and 8.52,2.99 and 3.06 at 6h in mice,respectively.In monkey brain imaging the ratios of striatum/frontal cortex(ST/FC)and striatum/occipital cortex(ST/OC) were 5.14 and 5.97 at 4h.respectively,All of above showed the high affinity of the ligand to DAT,The compound was primarily metabolized in liver because the hepatic uptake was much higher than other organs(75.4%ID/organ at 18h).The half-life of blood elimination was 5min.The dose received by mice was 2500 times as high as that received by human in the test of undue toxicity,which evaluated the safety of the agent.All the results suggest that β-CIT can be used as a potential DAT imaging agent.     

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。     

Comparative studies of D2 receptors and brain perfusion in hemi-parkinsonism rats

1 INTRODUCTIONParkinson's disease(PD) is characterized by selective loss of doptalnergic cellsin substantia nigra(SN) which project to striatum(ST), 14%~80% patients would accomphaed with dementia dUling their later stage of PD according to various statistic data, studies revealed deficit of regional cerebral blood flow (rCBF) and glucosemetabolism in frontal cortex etc. area in these patients[1]. The relationship betweencelltral dopalnine(DA) transactter system and brain perfusion i…     

Synthesis and labelling of epidepride

S-(-)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide(Proposed generic name,epidepride)is a very potent dopamine D2 antagonist.It was synthesized by five steps from 3-methoxysalicylic acid.[^131I]epidepride was obtained in 97.3% radiochemical yields from the corresponding 5-(tributylitin)derivative using hydrogen peroxide as the oxidant.The aryltin precursor was prepared from non-labelled epidepride by palladium-catalyzed stannylation using bis(tri-n-butyltin)in triethylamine.[^131I] epidepride was stable under 4℃,and partition coefficient was 72.3 at pH 7.40.The biodistribution study in rats exihibited high localization in the striatum of the rain with the striatum/cerebellum ratio reaching 237/1 at 320min postinjection.All these results suggest that[131I] epidepride may be used widely as a useful dopamine D2 receptor imaging agent for SPECT.     

Semi-automated synthesis, validation and microPET imaging of 18F-FP-DTBZ as a vesicular monoamine transporter ligand

This work was to develop a semi-automated synthesis of 18F-9-fluoropropyl-9-desmethyl-DTBZ (18F-FP-DTBZ) and validate its potential as a vesicular monoamine transporter 2 (VMAT2) ligand.18F-FP-DTBZ was synthesized by a semi-automated procedure in a 21-35% yield without decay correction and with a radiochemical purity of >98%.Bioistribution in rats exhibited a favorable brain uptakes of the ligand (0.31±0.04 ID% at 60min post injection,n=8).The highest radioactivity located in VMAT2 enriched striatal tissue.The target-to-nontarget ratio (striatum/cerebellum,ST/CB) was 4.81±0.84.Blocking studies implied that striatum uptake could be blocked by DTBZ (a VMAT2 inhibitor) but could not by CFT (a dopamine transporter inhibitor).MicroPET imaging with 18F-FP-DTBZ in normal rats gave high quality images in which high radioactivity were observed in the striatal tissue.Time-and-activity curves revealed good retention in the target (striatum) and rapid clearance in the background (cerebellum),which resulted in a maximum ST/CB ratio of 5.08±0.81 (n=3) in 80-120min.By contrast,the 6-hydroxydopamine unilateral lesioned rats gave asymmetrical striata images with higher 18F-FP-DTBZ concentration on the unlesioned side (unlesioned-ST/CB=5.21±0.38,n=3) than the lesioned (lesioned-ST/CB=2.34±0.51).The results validated that 18F-FP-DTBZ is a favorable PET ligand binding to VMAT2.     

Synthesis, radiolabeling and animal studies of [~(131)I]MPPI: A 5-HTB_(1A) imaging agent

1 Introduction In the last two decades, considerable progress has been made in the understanding of the central nervous system (CNS) serotonin system. It is an important neurotransmission network that regulates various physiological functions and behavior, including anxi-ety and affective states.P[1-3]P The family of receptors activated by the neurotransmitter serotonin has been divided into at least seven classes (5-HTB1-7B), some of them further subdivided into different subtypesP[4, 5]P…     

Synthesis, radiolabeling and animal studies of [131I]MPPI: A 5-HT1A imaging agent

The synthesis and biological evaluation of serotonin (5-HT1A) imaging agent [131I]-4-iodo-N-{2-[4-(2-methoxyphenyl)-piperazin-1-yl]-ethyl}-N-pridin-2-yl-benzamide ([131I]MPPI) are reported. The chemical structure of aimed compound and intermediates were confirmed by IR, 1HNMR, and MS. Radiochemical purity was above 99% determined by TLC. Biodistribution of [131I]MPPI in rats displayed high uptake in hippocampus and low uptake in cerebellum. The ratio of the uptake of [131I]MPPI in hippocampus to that in cerebellum was 2.90 at 30 min post injection. The radioactivity in thyroid was 0.069 and 0.128% ID/g organ at 5 min and 120 min,respectively, and it was increased with time, which suggests that in vivo deiodination may be the major route of metabolism. Ex vivo autoradiography of brain section displayed significant decrease of radioactivity in hippocampus when pretreated with 8-OH-DPAT, a selective 5HT1A agonist, compared with control. These findings strongly suggested that 131I-MPPI could be used as an in vivo marker for studies of pharmacology of the 5-HT1A receptor system in animals.