99mTc-放射性药物的现状和展望

分子影像技术和靶向人类疾病不同靶点以及反映特定生物过程的放射性核素标记的分子探针是实现精准医疗的最佳途径。^99mTc-放射性药物与其他SPECT药物以及PET药物在疾病的临床诊断与预后、治疗疗效评估中优势互补，发挥着重要作用。本文概述了临床上正在使用、处于临床试验阶段或临床研究阶段的^99mTc-放射性药物，分析了^99mTc-放射性药物的发展前景和发展趋势，提出继续探索新的靶点，加强基础锝配位化学研究等建议。只有不断研制出反映活体生物化学过程或特异靶向体内生物分子的新型^99mTc-放射性药物，同时发展适于临床使用的^99mTc-标记技术，才能加速新型^99mTc-放射性药物的临床转化，更好地为人类健康服务。     

Pharmacokinetics and radiation dosimetry of 99mTc-3PRGD2 in healthy individuals:A pilot study

^99mTc-3PRGD₂ is a new SPECT radiotracer for several tumor imaging with high uptake where integrinα_vβ₃ is highly expressed.This pilot study was to assess the safety,biodistribution and radiation dosimetry of 9,mTc-3PRGD2 in healthy volunteers.The 10 healthy male volunteers were injected with ^99mTc-3PRGD₂（786.7±55.8 MBq,19.1-24.2 mCi）.Baseline measurements of vital signs,laboratory safety tests and 12-lead electrocardiogram were recorded before and after injection.Blood and urine samples were collected and radiation counts were obtained at various time points.Whole-body scans and ROIs of identified organs were used for visual analysis and estimating the radiation dosimetry.No adverse reactions were found during the study.^99mTc-3PRGD₂ exhibited a rapid clearance from the blood with less than 45%of the initial dosage at 10 min after injection and gradual increasing radioactivity in urine with（52.9±6）%of original dose at 1440 min.The whole-body imaging showed high radioactive accumulation in bladder.And the highest ^99mTc-3PRGD₂ uptake was found in the kidneys(3.50×10^-2 mSv/MBq).The ^99mTc-3PRGD₂ exhibited good pharmacokinetic properties and little radiation burden.This study showed that ^99mTc-3PRGD₂ would be a safe and attractive SPECT agent in clinic applications.     

新型心肌灌注显像剂~(99)Tc~m-CO-MIBI与~(99)Tc~m-MIBI的药理学比较

以犬为实验动物,99Tcm-CO-MIBI和99Tcm-MIBI为显像剂,采用自身对照的方法,通过采集血样、采集动态图像和全身显像获得药物在犬体内的代谢动力学参数、生物分布、靶与非靶放射性摄取比和全身、心脏平面及断层影像等药效学结果。结果显示,99Tcm-CO-MIBI符合一次静脉给药的血药动力学二室开放模型,快相及慢相半衰期分别为Tα(1/2)=1.46±0.13 min,Tβ(1/2)=97.30±20.50 min,全血总清除率CL=436.36±54.77 mL/h。心、肺、肝时间-放射性曲线显示,在注射约40 min后,99Tcm-CO-MIBI肝脏曲线明显低于心肌曲线。多时间点心脏与肺脏及肝脏的放射性摄取比亦表明99Tcm-CO-MIBI在心肌摄取高,滞留久,肺本底低,肝脏药物排出比99Tcm-MIBI明显快。注射99Tcm-CO-MIBI后10~120 min内均可获得清晰的心肌图像,40 min后下壁心肌显示不再受肝内放射性干扰。表明99Tcm-CO-MIBI犬体内生物分布优异,有望成为一种新型心肌灌注显像剂。     

18F-NaF注射液的制备及新西兰兔骨折显像

由外伤或肿瘤骨转移造成的隐匿性骨折和愈合情况的准确诊断对制定合适的治疗方案具有非常重要的意义。为考查¹⁸F-NaF PET显像用于骨折诊断的诊断效能，本研究制备了¹⁸F-NaF注射液，并对其进行了质量控制和稳定性研究，然后建立新西兰兔骨折动物模型，模型建立约2周后进行了¹⁸F-NaF PET显像和⁹⁹Tc^m-亚甲基二磷酸盐（⁹⁹Tc^m-MDP）SPECT显像的自身对照实验，并对显像效果进行了比较。结果表明：¹⁸F-NaF的产量大于37 GBq，各项检验结果均符合质控要求，40 ℃下放置8 h和30 ℃下放置10 h所有检验结果均无明显变化；¹⁸F-NaF PET和⁹⁹Tc^m-MDP SPECT两种显像方式均可见全身骨骼，骨折部位呈明显放射性浓聚，但¹⁸F-NaF给药后30 min即可进行PET显像，骨折部位显示更为清晰，骨折部位与对侧正常骨骼的放射性摄取比（T/NT）明显高于⁹⁹Tc^m-MDP，而⁹⁹Tc^m-MDP需在给药后2 h才能进行SPECT显像。本研究表明¹⁸F-NaF PET对骨折的显像性能优于⁹⁹Tc^m-MDP，可明显提高检查流通量和诊断效能。     

A pilot study on ^99mTc-3PRGD2 scintigraphy in diagnosis of brain glioma

The ^99mTc-3PRGD₂ targeted SPECT/CT scanning was of significance in detecting differentiated glioma.In this work,the diagnostic value of ^99mTc-3PRGD₂ scintigraphy in brain glioma was evaluated by the ten clinically verified brain glioma patients after obtaining informed consent.The patients first accepted X-ray imaging to localize the detecting regions before administrating with ^99mTc-3PRGD₂ at a mean radioactivity of 849±115 MBq via single intravenous bolus injection 2 h prior to SPECT/CT imaging.Tumor samples for detectingαvβ3 were collected by surgical operations two weeks after the scintigraphy.The results of CT and SPECT scanning were merged and compared.The correlation between tumor occupation（T/N ratio） andαvβ3 expression level were analyzed.The T/N ratios in brain glioma were proportionally correlated to av(33 positive cell percentage（R²=0.9253,p<0.05）.This study primarily evaluated the clinical application of ^99mTc-3PRGD₂ SPECT scintigraphy on brain glioma.The more pathological types and detecting strategies covering a large amount of samples would aid to clarify the potentials.     

99mTc标记的前列腺特异性膜抗原抑制剂HYNIC-P137的制备与临床转化

为开发低膀胱滞留的前列腺癌SPECT显像剂，在⁶⁸Ga-P137结构的基础上制备了^99mTc-P137,对其进行临床前评估和初步的临床转化研究。通过固相合成方法制备标记前体HYNIC-P137,用EDDA作为共配体对前体进行^99mTc标记，并对产物^99mTc-P137进行质控。考察^99mTc-P137的脂水分配系数和体外稳定性，考察其在PSMA阳性细胞和阴性细胞上的摄取和抑制。进行正常昆明小鼠的生物分布和荷瘤鼠的SPECT/CT显像，最后进行临床转化研究。结果表明，前体HYNIC-P137的固相合成方便易得，标记产物^99mTc-P137的放化纯度接近100%,体外稳定性好，亲水性较强。正常昆明小鼠生物分布显示，该探针血液清除较快，主要通过肾脏代谢。荷瘤鼠的小动物SPECT/CT显示，^99mTc-P137主要在PSMA阳性肿瘤和肾脏区域浓集，且均可被明显抑制，显示出高度的体内特异性。临床转化显示，^99mTc-P13...     

99Tcm-CQDO和99Tcm-CQDO-MeB的小鼠体内分布和药代动力学比较

以氯化亚锡为还原剂制备了99Tcm-CQDO及其甲基硼酸加成物99Tcm-CQDO-MeB,经萃取纯化,其放化纯度均>90%.小鼠体内分布表明,两者均能被小鼠心肌迅速摄取;99Tcm-CQDO的心肌清除快,10min时已清除至(5.88±1.66)%ID/g;而99Tcm-CQDO-MeB在心肌内却有较长的滞留时间,60min时心肌摄取仍有(7.42±0.17)%ID/g.两者在血中清除均符合双指数二室模型,T1/2α分别为1.38min和1.51min.pH为7.40时,99Tcm-CQDO和99Tcm-CQDO-MeB的分配系数分别为25和12.     

~(99m)TcN-IBDTC与~(99m)Tc-IBDTC的对比研究

为了检验配合物分子中 [99mTcN]2 + 中心核的引入对其生物分布的影响以求找到一种新的放射性药物。采用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[99mTcN]2 + int 中间体 ,然后与配体N -异丁基 -二硫代氨基甲酸钠 (IBDTC)发生配体交换反应得到99mTcN -IBDTC配合物。同时采用甲脒亚磺酸 (FSA)作还原剂对配体IBDTC进行了99mTc直接标记。结果表明 ,99mTcN -IBDTC和99mTc -IBDTC配合物的放化纯均大于 90 % ,小鼠体内生物分布表明 ,99mTcN -IBDTC有较高的脑摄取和较好的脑滞留 ,在注射后 5、30、6 0min时脑摄取量 (%ID·g- 1)分别为 6 .2 2、5 .4 5、3.88,脑 /血比值分别为 1.5 1、2 .2 4、1.84 ,有望成为一类新型脑灌注显像剂。99mTcN -IBDTC在心肌中也有较高的摄取 ,但心肌清除快而且心 /肝比值低从而限制了其成为一类新型心肌灌注显像剂。99mTc -IBDTC主要在肝内浓集 ,而脑、心肌摄取很少。本实验提示 ,放射性药物分子中引入 [99mTcN]2 + 核会引起生物分布性质的明显改变 ,这对于设计新型放射性药物具有参考价值。     

正电子心肌灌注显像剂的临床应用及研究进展

随着正电子发射型断层显像仪（PET）及PET／CT在国内外的逐步推广应用，正电子心肌灌注显像剂的研究也备受关注，PET应用的心肌灌注显像剂有^82Rb ^13NH3和H2^16O，但半衰期均较短（t1/2〈10min），或需要^82Sr／^82Rb发生器或加速器等原因限制了其应用。近来长半衰期核素^18F标记的新型灌注类显像剂成为研究热点，报道较多的一类显像剂是以心肌细胞线粒体复合物-I（MC—I）为靶点，该类显像在动物体内外试验中均表现出良好的显像性能：心肌摄取快，血流灌注相关性好，滞留时间长。其中又以^18F-BMS747158—02最为突出，除具备上述特性外，还体现出心室放射性摄取均匀，体内生物分布理想的特点，有望成为较理想的正电子心肌灌注显像剂。     

18F-FDG PET/CT显像对心肌“缺血记忆”的分子机制研究

建立了不同程度的犬急性心肌缺血-再灌注模型。利用¹⁸F-FDG PET/CT动态心肌显像和实时定量PCR方法探讨了缺血心肌葡萄糖代谢改变（缺血记忆）和缺血程度的关系。将8只杂种犬随机分为球囊封堵20 min组（4只）和40 min组（4只）,在空腹状态下（禁食>12 h）行基础、缺血1 h和缺血24 h的¹⁸F-FDG PET/CT动态心肌显像以及⁹⁹Tc^m-MIBI SPECT心肌灌注显像。计算缺血区和非缺血区心肌的葡萄糖摄取率比值K。所有显像完成后处死实验犬并分别取缺血区、非缺血区心肌组织。应用实时定量PCR方法,测定葡萄糖转运体蛋白1、4（GLUT-1、GLUT-4）、心脏脂肪酸结合蛋白（H-FABP）基因的mRNA表达量。两组犬三次心肌灌注显像均未见异常。基础显像时,两组预封堵心肌与非缺血区心肌¹⁸F-FDG摄取率的比值K无明显差异;缺血1 h后,两组K值均增加,且40 min组高于20 min组;缺血24 h后,40 min组的K值仍高于基础状态,而20 min组的K值与基础状态下无明显差异。PCR结果示,两组非缺血心肌的GLUT-1、GLUT-4以及H-FABP基因mRNA表达量无明显差异,而缺血心肌的GLUT-1和GLUT-4基因mRNA表达量增加,H-FABP基因的mRNA表达量减低,且40 min组的改变较20 min组更为明显。以上结果提示,心肌缺血-再灌注后,缺血心肌对葡萄糖（¹⁸F-FDG）摄取增加的程度和持续时间（缺血记忆）与缺血的程度相关。     

~(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。     

Study of biodistribution properties of a new myocardial imaging agent [99mTc(N)(PNP5)(DBODC)]+

^99Tc^mN DBODC5 for intravenous injection was prepared. The labelling yield was 95.0%±0.52%. Sixteen New Zealand rabbits were involved and planar gamma imaging was performed at 10 time point after injection of ⁹⁹Tc^mN DBODC5. The radioactivity channes of organs were calculated by regions of interest (ROI) analysis. The 16 rabbits were divided into 4 groups and were sacrificed at 30, 60, 120, and 180 min after injection respectively. The activity for all excised organs were measured by γ well counting for calculating radiouptake. Myocardial uptake for 99Tcm N DBODC5 is high. Though myocardial uptake was lower than 99Tcm MIBI, the liver clearance for ⁹⁹Tc^mN DBODC5 was more rapid than that of ⁹⁹Tc^m MIBI. As early as 30 min after injection, ⁹⁹Tc^mNDBODC5 heart to liver ratio is 0.98±0.52 versus 0.56±0.19 for ^99Tc^m MIBI (P<0.01). At 60 min post injection, ^99Tc^mNDBODC5 heart to liver ratio improved to the peak value (1.18±0.57), compared with 0.71±0.29 for ⁹⁹Tc^m MIBI, P<0.01. After 60 min, the heart to liver ratio of ⁹⁹Tcm N DBODC5 was keeping at a high level until 180 min. ⁹⁹Tc^m N DBODC5 exhibited rapid lung clearance, similar to that of ⁹⁹Tc^m MIBI. The biodistribution in the isolated organs demonstrated the same trend. The rapid ⁹⁹Tc^m N DBODC5 liver clearance may allow the earlier imaging, and overcome the photon scatter from the liver with high activity which interfered the inferoapical wall in myocardial images. ⁹⁹Tc^m N DBODC5 is a promising new myocardial perfusion imaging agent with superior biodistribution properties.     

Preparation andBiodistribution of Myocardial Perfusion Imaging Agent 18F-TPT

⁹⁹Tc^m-sestamibi is typically used as amyocardial perfusion imaging agent for SPECT, however, the high uptake of liverand lung compromise the diagnostic accuracy. PET has higher spatial resolutionand quantitative measurement of myocardial tracer uptake. The lipophiliccationic compound, (4-[¹⁸F]fluorophenyl)triphenylphosphoniumion (¹⁸F-TPT)was synthesized as a potential positron emission tomography (PET) myocardialperfusion agent, biodistribution studies in the NH rats and Micro PET/CTimaging studies in the SD rats were performed. Total synthesis time was about 1h and the uncorrected synthesis yield was 2.5%, radiochemical purity was higherthan 99.5%, the product had good stability at room temperature. Biodistributiondata in rats showed high levels of accumulation in the heart with stableretention and rapid blood clearance, Heart-to-liver ratios at 30, 60, 90,and120 min were 33.1, 14.8, 25.7 and 17.3, respectively; Micro PET/CT imagingin the SD rat showed intense cardiac uptake and non-target tissues as liver,lung uptake were washed out quickly. The result show that ¹⁸F-TPT may have potential as amyocardial perfusion imaging agent for PET.     

Preparation and Biological Evaluation of Novel 18F-labeled Phosphonuim Cation for Myocardial Perfusion Imaging with PET

In order to develop new PET myocardial perfusion imaging agent, a novel¹⁸F labeled phosphonium cation: (3-(［¹⁸F］fluoromethyl)benzyl) tris (2, 6-dimethoxyphenyl) phosphonium salt, ¹⁸F-2, had been designed and prepared. Biological evaluation of¹⁸F-2 had been performed in Kunming normal mice.¹⁸F-2 was obtained by a simple one-pot method and the radiochemical yield was (31±3)%. The total radio-synthesis time was less than 60 min and the radiochemical purity of final radiotracer was more than 95%. The biodistribution of¹⁸F-2 displayed a high heart uptake and good retention. The heart uptake of¹⁸F-2 at 5 and 60 min post-injection were (53.88±7.45)%ID/g and (23.93±3.28)%ID/g, respectively.¹⁸F-2 exhibited low radio-accumulation in non-target tissues and rapid clearance in liver, lung and blood. The heart to liver, heart to lungs and heart to blood ratio values were 3.99, 3.80 and 9.17, respectively. The results indicated that¹⁸F-2 could be as a promising myocardial perfusion imaging agent for PET imaging.     

锝［99mTc］亚甲基二膦酸盐注射液细菌内毒素定量检测

为使用FC/ET型酶标分析仪对锝［^99mTc］亚甲基二膦酸盐注射液（^99mTc-MDP）的细菌内毒素含量进行定量检测,建立^99mTc-MDP的光度动态显色方法,本研究对不同衰变时间细菌内毒素检测结果的影响进行分析,对不同浓度的^99mTc-MDP供试品溶液进行细菌内毒素与鲎试剂之间光度反应的干扰实验。结果显示,供试品溶液稀释30倍后对光度法反应无干扰,细菌内毒素含量<0.600 EU/mL,符合2020版《中国药典》规定内毒素的含量<15 EU/mL;不同活度的^99mTc-MDP与衰变后溶液的细菌内毒素检测结果无变化。建立的^99mTc-MDP细菌内毒素定量检测法操作简单、重复性好、方法可靠,可用于^99mTc-MDP注射液的细菌内毒素定量检查。     

加速器直接生产99mTc的化学分离纯化研究现状

^99mTc（T_1/2＝6.01 h）是⁹⁹Mo的衰变子体,是目前核医学临床诊断应用最为广泛的放射性核素,其使用量约占所有诊断放射性同位素的80%。近年来,基于回旋加速器通过核反应¹⁰⁰Mo(p,2n)^99mTc直接生产^99mTc已经成为国际上比较认可的方法,具有不需要反应堆、无高浓缩铀、放射性废物少、不存在核扩散风险等优势。本文针对加速器直接生产技术所发展的几种^99mTc化学分离纯化方法进行了详细阐述,包括柱色谱分离、溶剂萃取、化学沉淀以及热色谱法。本工作可为我国开展加速器直接生产^99mTc提供一定的参考。     

18F-FDG符合显像诊断梗死心肌活力的实验研究

将6只20kg的小型猪制作心肌梗死模型,进行心肌99Tcm-甲氧基异丁基异腈(99Tcm-sestamibi,99Tcm-MIBI)血流灌注显像确定梗死区,用18F-脱氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)观察空腹与糖负荷图像的差别,确定心肌坏死或存活区.制作模型前进行自身对照形成对照组.并进行B超心功能检查.结果显示:心肌梗死区大部分心肌没有活力,99Tcm-MIBI和18F-FDG都没有摄取.空腹时有部分心肌显影,糖负荷时该区域显影程度减轻.     

新型心肌灌注显像剂99TcmNDBODC5在兔体内的生物分布

制备了99TcmNNBODC5，并将其经静脉注射到新西兰白兔体内，进行活体显像，检测其活体生物分布及离体器官分布，研究99TcmNDBODC5作为心肌灌注显像剂的可行性。活体生物分布结果显示，99TcmNDBODC5的心肌摄取迅速，心肌摄取量低于99TcmMIBI， 99TcmNDBODC5的肝清除速度显著快于99TcmMIBI，在注射后30 min时心与肝的T/NT为0.98±0.52,已接近1，显著高于99TcmMIBI的心与肝的T/NT(0.56±0.19)，P=0.007。60 min时，99TcmNDBODC5的心与肝的T/NT达到高峰,为1.18±0.57，而99TcmMIBI仅为0.71±0.29。在180 min内，99TcmNDBODC5的心与肝的T/NT维持在较高水平。99TcmNDBODC5的肺摄取低，清除快，心与肺的T/NT在180 min内保持在1.43±0.37以上，与99TcmMIBI无显著差别。99TcmNDBODC5的肝清除迅速，避免了肝内放射性对左室下壁的干扰，有利于实现早期显像。故99TcmNDBODC有望成为一种生物分布特性较好的新的心肌灌注显像剂。