新型心肌灌注显像剂［~（99m）Tc（N）（PNP5）（DBODC）］~+的动物实验研究
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摘要
在过去的二十多年中，为了克服~((201))Tl物理特性差的缺点，研究者一直致力于研究开发由物理特性极佳的~((99m))Tc标记的心肌灌注显像剂，几种新型心肌灌注显像剂相继研制成功并应用于临床。现有的~((99m))Tc标记心肌灌注显像剂依所负电荷的不同可分为两大类，即阳离子心肌灌注显像剂和中性心肌灌注显像剂。目前，临床上使用最广泛的~((99m))Tc标记心肌灌注显像剂~((99m))Tc-MIBI和~((99m))Tc-tetrofosmin均为单价阳离子配合物，它们均具有较高的心肌摄取和满意的心肌滞留时间；~((99m))Tc-teboroxime和~((99m))TcN-NOET是两个中性心肌灌注显像剂，它们的心肌提取率高，在高血流状态下更能准确地反映冠状动脉血流状况，且它们均具有和~((201))Tl相似的“再分布”现象。~((99m))TcN-NOET还是第一个报道的具有稳定的[~((99m))Tc≡N]~((2+))核结构的心肌灌注显像剂。
尽管这些~((99m))Tc标记心肌灌注显像剂的物理特性明显优于~((201))Tl，但它们均具有一个共同的缺点就是它们的生物分布特性都不理想，肝脏摄取放射性高，清除缓慢，不仅导致显像时间延长，而且由于肝脏距离心脏较近，持续的肝浓聚会明显干扰左室下后壁及心尖部的清晰显影。因此，研究开发生物分布特性更好的~((99m))Tc标记心肌灌注显像剂仍然具有重要的现实意义。
[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) ((二(二甲基丙基膦基乙基)-乙氧乙胺)-(二(氮-乙氧乙基)二硫代氨基)锝氮配合物)是新近开发出的一类~((99m))Tc标记心肌灌注显像剂。与~((99m))TcN-NOET类似，它也是一个以[~((99m))Tc≡N]~((2+))核结构为中心的脂溶性配合物，但与~((99m))TcN-NOET不同的是，它是一个单价阳离子显像剂，这一点又与~((99m))Tc-MIBI和~((99m))Tc-tetrofosmin相似。早期研究显示，该化合物具有较高的亲心肌特性和显著的肝清除速度，生物分布特性优于~((99m))Tc-MIBI和~((99m))Tc-tetrofosmin。
本研究的目的就是通过动物实验进一步研究[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的生物分布特性及药代动力学特征，以及它在急性心肌缺血模型中的显像特点，以便对该配合物作为一种新的心肌灌注显像剂用于临床的可能性做出初步评价。
第一部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
在兔体内的生物分布研究
目的：研究新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在兔体内的生物分布特性。
方法：利用药盒法制备的[~((99m))Tc(N)(PNP5)(DBODC)]~((+))注射液，放化纯(95．0±0．52)％。新西兰兔16只，于静脉注射显像剂后不同时间，进行全身平面显像，利用感兴趣区技术计算各器官放射性活度的变化。16只兔随机分为4组，分别在注射后30，60，120和180min处死，取各脏器称重并测量放射性计数。
结果：活体生物分布研究显示，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心肌摄取虽然较高，但在整个显像时间内始终低于~((99m))Tc-MIBI。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肺摄取值低，清除快，在180min内心朋市比值一直保持在较高水平，与~((99m))Tc-MIBI无显著差别。尤其重要的是，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除速度显著快于~((99m))Tc-MIBI，在注射后30min心／肝比值已接近1，显著高于~((99m))Tc-MIBI(0．98±0．52对0．56±0．19，p=0．007)。60min时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值达到高峰(1．18±0．57)，~((99m))Tc-MIBI为0．71±0．29。此后，在180min内，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值维持在较高水平。离体器官生物分布研究显示出了相同的趋势，即肺摄取低，清除快，肝脏摄取呈一过性，从而可以很快获得满意的靶／非靶比值。
结论：由于[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除迅速，这不仅避免了肝内放射性对左室下壁的干扰，而且有利于实现早期显像。故[~((99m))Tc(N)(PNP5)(DBODC)]~((+))有望成为一种生物分布特性较好的新的心肌灌注显像剂。
第二部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
猪心肌显像的实验研究
目的：评价新型心肌显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在猪体内的药代动力学特征及生物分布特性。
方法：利用药盒法制备[~((99m))Tc(N)(PNP5)(DBODC)]~((+))注射液，标记率(95．54±0．85)％。实验动物选用7只实验用中华小型猪，由耳静脉注入[~((99m))Tc(N)(PNP5)(DBODC)]~((+))，分别于注射后2、5、10、15、30、45、60、75、90、120、150和180min从猪下肢静脉进行血样采集以获得药代动力学参数，同时进行胸腹部平面系列显像以观察该药物在猪体内的生物分布和靶／非靶比值。
结果：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))符合一次静脉给药的药代动力学二室模型，分布半衰期T_((1/2α))=(2．97±0．48)min，消除半衰期T_((1／2β))=(52．49±19．49)min，血液总清除速率CL=(14314．29±8445．79)ml／h。心、肝、肺时间一放射性曲线显示[~((99m))Tc(N)(PNP5)(DBODC)]~((+))肝摄取曲线在初始时明显高于心肌曲线，但肝内放射性清除迅速，在注射30min以后，肝内放射性已低于心肌放射性，而~((99m))Tc-MIBI的肝曲线在180min的显像时间内均高于心肌曲线。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值在注射后30min至180min的时间内均显著高于~((99m))Tc-MIBI(p<0．05)。平面系列显像显示，在注射[~((99m))Tc(N)(PNP5)(DBODC)]~((+))后5～180min均可获得清晰的心肌图像，肝脏内放射性迅速排入胆、肠系统，致使肝内放射性迅速减低，有利于减少对左室下壁的干扰，同时利于实现早期显像。
结论：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))有望成为一种新的心肌灌注显像剂。
第三部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
犬急性心肌缺血模型的显像研究
目的：观察新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在犬急性心肌缺血模型中的显像特点。
方法：12只实验用纯种比格犬随机分为两组。组1，手术结扎左冠状动脉前降支(LAD)制成冠脉狭窄>90％后，静脉滴注腺苷，0．14mg／kg·min，共6min，3min末时注射[~((99m))Tc(N)(PNP5)(DBODC)]~((+))185MBq。腺苷滴注完毕后，解除结扎线，恢复心肌供血。分别于注射显像剂后0．5，1，1．5和2hr进行心肌灌注SPECT显像，24hr后进行静息心肌SPECT显像。组2，除注射的显像剂为~((99m))Tc-MIBI外，其余实验方案同组1。
结果：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心肌摄取高，滞留时间长，其心肌摄取与~((99m))Tc-MIBI相当。两者的肺摄取均很低(0．5hr时，[99mrc(N)(PNP5)(DBODC)】+和99mTc-MIBI的。时肺比佰分别为3和32，目内无显著变化)。但．55+0．68 2．92+0．2hr[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除速度显著快于~((99m))Tc-MIBI(注射后1hr时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值已显著高于~((99m))Tc-MIBI，1．364±0．43对0．58±0．21，p=0．005)。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))能清晰显示心肌缺血，其检测心肌缺血的效能与~((99m))Tc-MIBI相当([~((99m))Tc(N)(PNP5)(DBODC)]~((+))显示缺损节段3．60±1．52个，~((99m))Tc-MIBI显示缺损节段4．25±0．96个，p=0．48)。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))具有和~((99m))Tc-MIBI相似的轻度“再分布”特性。由于肝清除迅速，早期显像时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的图像质量优于~((99m))Tc-MIBI。
结论：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))作为一种新型心肌灌注显像剂，它的心肌摄取、肺摄取、检测心肌缺血的效能以及“再分布”特性等均与~((99m))Tc-MIBI相似，同时，它的肝清除速度却显著快于~((99m))Tc-MIBI，这不仅有利于实现早期显像，而且避免了肝摄取对左室下后壁的干扰，从而利于更准确地诊断冠心病。故[~((99m))Tc(N)(PNP5)(DBODC)]~((+))具有进一步进行临床研究的价佰。
In order to circumvent the physical limitations (low-energy photons and long half-life)of ~((201))Tl, investigators have been attempted to develop suitable myocardial perfusion agentslabeled with technetium-99m (~((99m))Tc), a radioisotope with ideal physical properties forscintillation camera imaging. In the last two decades, great advances have been achieved,several kinds of ~((99m))Tc-labeled myocardial perfusion imaging agents have been developedand used clinically. Cationic ~((99m))Tc compounds, ~((99m))Tc-MIBI and ~((99m))Tc-tetrofosmin areroutinely used for clinical imaging with their favorable myocardial uptake and retentionproperties. Neutrally charged ~((99m))Tc complexes, ~((99m))Tc-teboromixe and ~((99m))TcN-NOET, exhibitbetter flow-extraction properties at high flows compared with these cationic agents and havecomplete redistribution similar to ~((201))Tl. Moreover, ~((99m))TcN-NOET is the first reportedcompound characterized by the presence of a terminal technetium-nitrogen multiple bond.
Although the physical properties of ~((99m))Tc are better suited than ~((201))Tl forγ-cameraimaging, the organ biodistribution properties of these ~((99m))Tc-labeled tracers remainsuboptimal for myocardial perfusion imaging. Intense liver uptake and slow liver clearanceprolong the duration of imaging protocols. In particular, because of its close proximity to theheart, prolonged high liver uptake can make it difficult to accurately assess myocardialperfusion, particularly in the inferior or inferoapical left ventricular wall. Therefore, it isimportant to develop new tracers with improved organ biodistribution properties, with lessliver uptake.
[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) (technetium 99m [bis (dimethoxypropylphosphinoethyl)ethoxyethylamine]-[bis (N-ethoxyethyl) dithiocarbamato] nitride) is a new class nitrido~((99m))Tc agent that is currently under investigation. The core of this molecule consists of ~((99m))Tctriple bonded to nitrogen, and it is lipophilic, similar to ~((99m))TcN-NOET. However, unlike~((99m))TcN-NOET, which is a neutral molecule, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is monocationic,like ~((99m))Tc-MIBI and ~((99m))Tc-tetrofosmin.
The goal of this experimental study was to determine the organ biodistribution andpharmacokinetics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)), and to assess the characteristics of itsmyocardial imaging in canine models of acute myocardial ischemia. On the basis of thesestudies, we can evaluate preliminarily whether this compound can be used clinically as amyocardial perfusion imaging agent.
PARTⅠStudy of biodistribution properties of a new myocardial imaging agent [~((99m))Tc(N)(PNP5)(DBODC)]~((+))
Objective: To study the biodistfibution properties of a new myocardial perfusion imagingagent [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in rabbit models.
Methods: Solution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) for intravenous injection was prepared.The radiochemical purity was (95±0.52)%. Sixteen New Zealand rabbits were involved.Planar gamma imaging was performed at different times after the injection of imaging agent.The radioactivity changes of organs were calculated using regions of interest (ROI)technique. The 16 rabbits were divided into 4 groups and were executed at either 30, 60, 120,or 180 min after injection andγ-well counting was performed on excised organs.
Results: Biodistribution in living rabbits showed, myocardial [~((99m))Tc(N)(PNP5)(DBODC)]~((+))uptake was high, but it was lower than ~((99m))Tc-MIBI during the whole imaging time.[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) exhibited rapid lung clearance, similar to ~((99m))Tc-MIBI.Importantly, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) cleared more rapidly from the liver than~((99m))Tc-MIBI. As early as 30min after injection, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) heart-to-liverratio was nearly 1 (0.98±0.52) versus 0.56±0.19 for ~((99m))Tc-MIBI (p<0.01). By 60min,[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) heart-to-liver ratio climbed to the peak (1.18±0.57) comparedwith 0.71±0.29 for ~((99m))Tc-MIBI (p<0.01). After 60min, the heart-to-liver ratio of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) kept in high level until 180min. The biodistribution in theisolated organs demonstrated the same trend.
Conclusion: The rapid [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) liver clearance may shorten theduration of imaging protocols by allowing earlier image acquisition and may markedlyreduce the problem of photon scatter from the liver into the inferoapical wall on myocardialimages. So [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is a promising new myocardial perfusion tracerwith superior biodistribution properties.
PARTⅡExperimental study of a new myocardial perfusion imaging agent [~((99m))Tc(N)(PNPS)(DBODC)]~((+)) in swine
Objective: To determine the pharmacokinetics and organ biodistribution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in swine.
Methods: Solution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) for intravenous injection was prepared.The average labeling yield was (95.54±0.85)%. The pharmacokinetics, biodistribution andratio of T/NT were studied in 7 swine. The tracer was injected from the ear vein. Samples ofblood were collected from the femoral vein at 2, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150 and180min, serial plane images were acquired meanwhile.
Results: The pharmacokinetics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) conformed totwo-compartment model, T_((1/2α))=(2.97±0.48)min, T_((1/2β))=(52.49±19.49)min, CL=(14314.29±8445.79)ml/h. The time-radioactivity curves showed that the liver uptake curves of[~((99m))Tc(N)(PNPS)(DBODC)]~((+)) were below the myocardial curves after 30min post-injection,while that of ~((99m))Tc-MIBI were above the myocardial curves. The heart to liver activity ratioof the new agent was higher than ~((99m))Tc-MIBI during 30min～180min (p<0.05). The planarimages of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) from 5 to 180min showed good quality with lowerlung and liver radioactivities. The rapid liver clearance of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) notonly may reduce photon scatter from the liver into the inferior walls on myocardial perfusionimaging, but also may shorten the duration of imaging protocols.
Conclusion: The results of this study show that the [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is veryworth further investigation as a potential myocardial perfusion imaging agent.
PARTⅢMyocardial perfusion imaging with [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in canine model of acute myocardial ischemia
Objective: To assess the characteristics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) myocardial imagingin canine models of acute myocardial ischemia, and compared with ~((99m))Tc-MIBI.
Methods: Twelve adult beagle dogs were included in this study. The left anterior descendingartery (LAD) was occluded to make a critical stenosis (>90%), then, adenosine was infusedintravenously at a rate of 0.14mg/kg-min for 6min. At the end of 3min of adenosine infusion,185MBq of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) or ~((99m))Tc-MIBI (randomly) was injectedintravenously. The occluder was released after adenosine infusion. Serial myocardial SPECT imaging acquisitions were obtained 0.5, 1, 1.5 and 2hr after tracer injection, respectively.Rest myocardial SPECT imaging was acquired in the next day.
Results: [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) exhibited high heart uptake and minimal lung uptake,that was similar with ~((99m))Tc-MIBI. No significant myocardial washout was observed withboth tracers over a period of 2 hours. [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) clearance from the liverwas obviously more rapid than that with ~((99m))Tc-MIBI (heart-liver radio at 60min, 1.36±0.43versus 0.58±0.21, p=0.005). [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) could detect myocardial ischemia,and the ability of it to detect myocardial ischemia was comparable to ~((99m))Tc-MIBI([~((99m))Tc(N)(PNP5)(DBODC)]~((+)) detected 3.60±1.52 defect segments, ~((99m))Tc-MIBI detected4.25±0.96 defect segments, p=0.48). Like ~((99m))Tc-MIBI, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) showedminimal redistribution. The image quality of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) was better than~((99m))Tc-MIBI.
Conclusion: With the exception of the more rapid liver clearance, many of the properties of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) that were observed in this canine study were comparable tothose of ~((99m))Tc-MIBI. So [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is a very promising new myocardialperfusion imaging agent for further clinical study.
Final conclusion: These studies indicated favorable heart uptake and retention of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in different animal species. Its lung uptake was low.Importantly, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) clearance from the liver was obviously more rapidthan that with ~((99m))Tc-MIBI. At rest and after pharmaceutical stress, favorable ratio of T/NTcould be acquired as early as 30min postinjection. The biodistribution properties of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) were superior to ~((99m))Tc-MIBI, and its ability to detectmyocardial ischemia was comparable to ~((99m))Tc-MIBI. Combining all of the favorableproperties of ~((99m))Tc-MIBI with more rapid liver clearance makes [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) a very promising new agent for clinical myocardial perfusion imaging.
尽管这些~((99m))Tc标记心肌灌注显像剂的物理特性明显优于~((201))Tl，但它们均具有一个共同的缺点就是它们的生物分布特性都不理想，肝脏摄取放射性高，清除缓慢，不仅导致显像时间延长，而且由于肝脏距离心脏较近，持续的肝浓聚会明显干扰左室下后壁及心尖部的清晰显影。因此，研究开发生物分布特性更好的~((99m))Tc标记心肌灌注显像剂仍然具有重要的现实意义。
[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) ((二(二甲基丙基膦基乙基)-乙氧乙胺)-(二(氮-乙氧乙基)二硫代氨基)锝氮配合物)是新近开发出的一类~((99m))Tc标记心肌灌注显像剂。与~((99m))TcN-NOET类似，它也是一个以[~((99m))Tc≡N]~((2+))核结构为中心的脂溶性配合物，但与~((99m))TcN-NOET不同的是，它是一个单价阳离子显像剂，这一点又与~((99m))Tc-MIBI和~((99m))Tc-tetrofosmin相似。早期研究显示，该化合物具有较高的亲心肌特性和显著的肝清除速度，生物分布特性优于~((99m))Tc-MIBI和~((99m))Tc-tetrofosmin。
本研究的目的就是通过动物实验进一步研究[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的生物分布特性及药代动力学特征，以及它在急性心肌缺血模型中的显像特点，以便对该配合物作为一种新的心肌灌注显像剂用于临床的可能性做出初步评价。
第一部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
在兔体内的生物分布研究
目的：研究新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在兔体内的生物分布特性。
方法：利用药盒法制备的[~((99m))Tc(N)(PNP5)(DBODC)]~((+))注射液，放化纯(95．0±0．52)％。新西兰兔16只，于静脉注射显像剂后不同时间，进行全身平面显像，利用感兴趣区技术计算各器官放射性活度的变化。16只兔随机分为4组，分别在注射后30，60，120和180min处死，取各脏器称重并测量放射性计数。
结果：活体生物分布研究显示，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心肌摄取虽然较高，但在整个显像时间内始终低于~((99m))Tc-MIBI。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肺摄取值低，清除快，在180min内心朋市比值一直保持在较高水平，与~((99m))Tc-MIBI无显著差别。尤其重要的是，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除速度显著快于~((99m))Tc-MIBI，在注射后30min心／肝比值已接近1，显著高于~((99m))Tc-MIBI(0．98±0．52对0．56±0．19，p=0．007)。60min时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值达到高峰(1．18±0．57)，~((99m))Tc-MIBI为0．71±0．29。此后，在180min内，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值维持在较高水平。离体器官生物分布研究显示出了相同的趋势，即肺摄取低，清除快，肝脏摄取呈一过性，从而可以很快获得满意的靶／非靶比值。
结论：由于[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除迅速，这不仅避免了肝内放射性对左室下壁的干扰，而且有利于实现早期显像。故[~((99m))Tc(N)(PNP5)(DBODC)]~((+))有望成为一种生物分布特性较好的新的心肌灌注显像剂。
第二部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
猪心肌显像的实验研究
目的：评价新型心肌显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在猪体内的药代动力学特征及生物分布特性。
方法：利用药盒法制备[~((99m))Tc(N)(PNP5)(DBODC)]~((+))注射液，标记率(95．54±0．85)％。实验动物选用7只实验用中华小型猪，由耳静脉注入[~((99m))Tc(N)(PNP5)(DBODC)]~((+))，分别于注射后2、5、10、15、30、45、60、75、90、120、150和180min从猪下肢静脉进行血样采集以获得药代动力学参数，同时进行胸腹部平面系列显像以观察该药物在猪体内的生物分布和靶／非靶比值。
结果：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))符合一次静脉给药的药代动力学二室模型，分布半衰期T_((1/2α))=(2．97±0．48)min，消除半衰期T_((1／2β))=(52．49±19．49)min，血液总清除速率CL=(14314．29±8445．79)ml／h。心、肝、肺时间一放射性曲线显示[~((99m))Tc(N)(PNP5)(DBODC)]~((+))肝摄取曲线在初始时明显高于心肌曲线，但肝内放射性清除迅速，在注射30min以后，肝内放射性已低于心肌放射性，而~((99m))Tc-MIBI的肝曲线在180min的显像时间内均高于心肌曲线。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值在注射后30min至180min的时间内均显著高于~((99m))Tc-MIBI(p<0．05)。平面系列显像显示，在注射[~((99m))Tc(N)(PNP5)(DBODC)]~((+))后5～180min均可获得清晰的心肌图像，肝脏内放射性迅速排入胆、肠系统，致使肝内放射性迅速减低，有利于减少对左室下壁的干扰，同时利于实现早期显像。
结论：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))有望成为一种新的心肌灌注显像剂。
第三部分：新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))
犬急性心肌缺血模型的显像研究
目的：观察新型心肌灌注显像剂[~((99m))Tc(N)(PNP5)(DBODC)]~((+))在犬急性心肌缺血模型中的显像特点。
方法：12只实验用纯种比格犬随机分为两组。组1，手术结扎左冠状动脉前降支(LAD)制成冠脉狭窄>90％后，静脉滴注腺苷，0．14mg／kg·min，共6min，3min末时注射[~((99m))Tc(N)(PNP5)(DBODC)]~((+))185MBq。腺苷滴注完毕后，解除结扎线，恢复心肌供血。分别于注射显像剂后0．5，1，1．5和2hr进行心肌灌注SPECT显像，24hr后进行静息心肌SPECT显像。组2，除注射的显像剂为~((99m))Tc-MIBI外，其余实验方案同组1。
结果：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心肌摄取高，滞留时间长，其心肌摄取与~((99m))Tc-MIBI相当。两者的肺摄取均很低(0．5hr时，[99mrc(N)(PNP5)(DBODC)】+和99mTc-MIBI的。时肺比佰分别为3和32，目内无显著变化)。但．55+0．68 2．92+0．2hr[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的肝清除速度显著快于~((99m))Tc-MIBI(注射后1hr时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的心／肝比值已显著高于~((99m))Tc-MIBI，1．364±0．43对0．58±0．21，p=0．005)。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))能清晰显示心肌缺血，其检测心肌缺血的效能与~((99m))Tc-MIBI相当([~((99m))Tc(N)(PNP5)(DBODC)]~((+))显示缺损节段3．60±1．52个，~((99m))Tc-MIBI显示缺损节段4．25±0．96个，p=0．48)。[~((99m))Tc(N)(PNP5)(DBODC)]~((+))具有和~((99m))Tc-MIBI相似的轻度“再分布”特性。由于肝清除迅速，早期显像时，[~((99m))Tc(N)(PNP5)(DBODC)]~((+))的图像质量优于~((99m))Tc-MIBI。
结论：[~((99m))Tc(N)(PNP5)(DBODC)]~((+))作为一种新型心肌灌注显像剂，它的心肌摄取、肺摄取、检测心肌缺血的效能以及“再分布”特性等均与~((99m))Tc-MIBI相似，同时，它的肝清除速度却显著快于~((99m))Tc-MIBI，这不仅有利于实现早期显像，而且避免了肝摄取对左室下后壁的干扰，从而利于更准确地诊断冠心病。故[~((99m))Tc(N)(PNP5)(DBODC)]~((+))具有进一步进行临床研究的价佰。
In order to circumvent the physical limitations (low-energy photons and long half-life)of ~((201))Tl, investigators have been attempted to develop suitable myocardial perfusion agentslabeled with technetium-99m (~((99m))Tc), a radioisotope with ideal physical properties forscintillation camera imaging. In the last two decades, great advances have been achieved,several kinds of ~((99m))Tc-labeled myocardial perfusion imaging agents have been developedand used clinically. Cationic ~((99m))Tc compounds, ~((99m))Tc-MIBI and ~((99m))Tc-tetrofosmin areroutinely used for clinical imaging with their favorable myocardial uptake and retentionproperties. Neutrally charged ~((99m))Tc complexes, ~((99m))Tc-teboromixe and ~((99m))TcN-NOET, exhibitbetter flow-extraction properties at high flows compared with these cationic agents and havecomplete redistribution similar to ~((201))Tl. Moreover, ~((99m))TcN-NOET is the first reportedcompound characterized by the presence of a terminal technetium-nitrogen multiple bond.
Although the physical properties of ~((99m))Tc are better suited than ~((201))Tl forγ-cameraimaging, the organ biodistribution properties of these ~((99m))Tc-labeled tracers remainsuboptimal for myocardial perfusion imaging. Intense liver uptake and slow liver clearanceprolong the duration of imaging protocols. In particular, because of its close proximity to theheart, prolonged high liver uptake can make it difficult to accurately assess myocardialperfusion, particularly in the inferior or inferoapical left ventricular wall. Therefore, it isimportant to develop new tracers with improved organ biodistribution properties, with lessliver uptake.
[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) (technetium 99m [bis (dimethoxypropylphosphinoethyl)ethoxyethylamine]-[bis (N-ethoxyethyl) dithiocarbamato] nitride) is a new class nitrido~((99m))Tc agent that is currently under investigation. The core of this molecule consists of ~((99m))Tctriple bonded to nitrogen, and it is lipophilic, similar to ~((99m))TcN-NOET. However, unlike~((99m))TcN-NOET, which is a neutral molecule, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is monocationic,like ~((99m))Tc-MIBI and ~((99m))Tc-tetrofosmin.
The goal of this experimental study was to determine the organ biodistribution andpharmacokinetics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)), and to assess the characteristics of itsmyocardial imaging in canine models of acute myocardial ischemia. On the basis of thesestudies, we can evaluate preliminarily whether this compound can be used clinically as amyocardial perfusion imaging agent.
PARTⅠStudy of biodistribution properties of a new myocardial imaging agent [~((99m))Tc(N)(PNP5)(DBODC)]~((+))
Objective: To study the biodistfibution properties of a new myocardial perfusion imagingagent [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in rabbit models.
Methods: Solution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) for intravenous injection was prepared.The radiochemical purity was (95±0.52)%. Sixteen New Zealand rabbits were involved.Planar gamma imaging was performed at different times after the injection of imaging agent.The radioactivity changes of organs were calculated using regions of interest (ROI)technique. The 16 rabbits were divided into 4 groups and were executed at either 30, 60, 120,or 180 min after injection andγ-well counting was performed on excised organs.
Results: Biodistribution in living rabbits showed, myocardial [~((99m))Tc(N)(PNP5)(DBODC)]~((+))uptake was high, but it was lower than ~((99m))Tc-MIBI during the whole imaging time.[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) exhibited rapid lung clearance, similar to ~((99m))Tc-MIBI.Importantly, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) cleared more rapidly from the liver than~((99m))Tc-MIBI. As early as 30min after injection, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) heart-to-liverratio was nearly 1 (0.98±0.52) versus 0.56±0.19 for ~((99m))Tc-MIBI (p<0.01). By 60min,[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) heart-to-liver ratio climbed to the peak (1.18±0.57) comparedwith 0.71±0.29 for ~((99m))Tc-MIBI (p<0.01). After 60min, the heart-to-liver ratio of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) kept in high level until 180min. The biodistribution in theisolated organs demonstrated the same trend.
Conclusion: The rapid [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) liver clearance may shorten theduration of imaging protocols by allowing earlier image acquisition and may markedlyreduce the problem of photon scatter from the liver into the inferoapical wall on myocardialimages. So [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is a promising new myocardial perfusion tracerwith superior biodistribution properties.
PARTⅡExperimental study of a new myocardial perfusion imaging agent [~((99m))Tc(N)(PNPS)(DBODC)]~((+)) in swine
Objective: To determine the pharmacokinetics and organ biodistribution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in swine.
Methods: Solution of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) for intravenous injection was prepared.The average labeling yield was (95.54±0.85)%. The pharmacokinetics, biodistribution andratio of T/NT were studied in 7 swine. The tracer was injected from the ear vein. Samples ofblood were collected from the femoral vein at 2, 5, 10, 15, 30, 45, 60, 75, 90, 120, 150 and180min, serial plane images were acquired meanwhile.
Results: The pharmacokinetics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) conformed totwo-compartment model, T_((1/2α))=(2.97±0.48)min, T_((1/2β))=(52.49±19.49)min, CL=(14314.29±8445.79)ml/h. The time-radioactivity curves showed that the liver uptake curves of[~((99m))Tc(N)(PNPS)(DBODC)]~((+)) were below the myocardial curves after 30min post-injection,while that of ~((99m))Tc-MIBI were above the myocardial curves. The heart to liver activity ratioof the new agent was higher than ~((99m))Tc-MIBI during 30min～180min (p<0.05). The planarimages of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) from 5 to 180min showed good quality with lowerlung and liver radioactivities. The rapid liver clearance of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) notonly may reduce photon scatter from the liver into the inferior walls on myocardial perfusionimaging, but also may shorten the duration of imaging protocols.
Conclusion: The results of this study show that the [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is veryworth further investigation as a potential myocardial perfusion imaging agent.
PARTⅢMyocardial perfusion imaging with [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in canine model of acute myocardial ischemia
Objective: To assess the characteristics of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) myocardial imagingin canine models of acute myocardial ischemia, and compared with ~((99m))Tc-MIBI.
Methods: Twelve adult beagle dogs were included in this study. The left anterior descendingartery (LAD) was occluded to make a critical stenosis (>90%), then, adenosine was infusedintravenously at a rate of 0.14mg/kg-min for 6min. At the end of 3min of adenosine infusion,185MBq of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) or ~((99m))Tc-MIBI (randomly) was injectedintravenously. The occluder was released after adenosine infusion. Serial myocardial SPECT imaging acquisitions were obtained 0.5, 1, 1.5 and 2hr after tracer injection, respectively.Rest myocardial SPECT imaging was acquired in the next day.
Results: [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) exhibited high heart uptake and minimal lung uptake,that was similar with ~((99m))Tc-MIBI. No significant myocardial washout was observed withboth tracers over a period of 2 hours. [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) clearance from the liverwas obviously more rapid than that with ~((99m))Tc-MIBI (heart-liver radio at 60min, 1.36±0.43versus 0.58±0.21, p=0.005). [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) could detect myocardial ischemia,and the ability of it to detect myocardial ischemia was comparable to ~((99m))Tc-MIBI([~((99m))Tc(N)(PNP5)(DBODC)]~((+)) detected 3.60±1.52 defect segments, ~((99m))Tc-MIBI detected4.25±0.96 defect segments, p=0.48). Like ~((99m))Tc-MIBI, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) showedminimal redistribution. The image quality of [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) was better than~((99m))Tc-MIBI.
Conclusion: With the exception of the more rapid liver clearance, many of the properties of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) that were observed in this canine study were comparable tothose of ~((99m))Tc-MIBI. So [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) is a very promising new myocardialperfusion imaging agent for further clinical study.
Final conclusion: These studies indicated favorable heart uptake and retention of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) in different animal species. Its lung uptake was low.Importantly, [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) clearance from the liver was obviously more rapidthan that with ~((99m))Tc-MIBI. At rest and after pharmaceutical stress, favorable ratio of T/NTcould be acquired as early as 30min postinjection. The biodistribution properties of[~((99m))Tc(N)(PNP5)(DBODC)]~((+)) were superior to ~((99m))Tc-MIBI, and its ability to detectmyocardial ischemia was comparable to ~((99m))Tc-MIBI. Combining all of the favorableproperties of ~((99m))Tc-MIBI with more rapid liver clearance makes [~((99m))Tc(N)(PNP5)(DBODC)]~((+)) a very promising new agent for clinical myocardial perfusion imaging.
引文
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