目前国内外临床上使用的99mTc脑灌注显像剂99mTc-d,l-HMPAO、99mTcO-L,L- ECD虽已经获得广泛应用，但是各自还存在不足，并且国内对于放射性药物仍是处在仿制阶段，因此研制出与国际先进水平相当的、具有我国自主知识产权的99mTc放射性药物是当务之急。在参与99mTcO-MPBDA研制工作的基础上，进一步对药物上临床前的工作进行完善。经过一系列对标记方法的改进，以及动物实验、人体显像实验，发现以γ环糊精作为助溶剂可以提高脑摄取值34.6%，并且将脑-血比值提高了1~2倍。制备了以溴离子为单齿配体，环糊精为助溶剂的99mTcO-MPBDA- Br，小鼠动物实验证实它在脑摄取、脑-血比值方面都优于原来标记方法制备的99mTcO-MPBDA-Cl。以一只健康成年雌性猕猴为动物模型测量全脑血流量的实验结果表明，99mTcO-MPBDA能够比较准确地测定脑血流量；志愿者人体显像实验中，脑灌注显像效果较好，可以用于临床诊断。99mTcO-MPBDA的体外稳定性优于99mTc-d,l-HMPAO，滞留性质好于99mTcO-L,L-ECD，注射后70min入脑量仍有3.45%ID。尽管初始脑摄取与99mTcO-L,L-ECD相比稍低，但是克服了99mTcO-L,L-ECD的酶水解滞留机制受到酶分布影响的缺点，并且具有我国完全自主的知识产权，可以申报新药，作为脑显像剂的一个新品种。通过一系列条件实验制备了99mTc-MPBDA的药盒，在室温下贮藏半个月后，其标记率仍然大于95%。而且小鼠动物分布实验结果表明，药盒化过程中甘露醇的引入不但没有改变99mTcO-MPBDA优良的脑摄取、脑滞留性质，反而加快了血清除过程，使脑-血比值随着时间的推移有很大提高，对于脑显像非常有利。药盒完全可以用于临床实验。成功地合成了尚无文献报道的两种新的三齿配体――MPTDA、MPDAA，并经过了红外、核磁、质谱的表征。通过摸索标记条件，制备了标记率大于95%的99mTcO-MPTDA、99mTcO-MPDAA。进而合成了加入不同卤素阴离子的99mTcO-MPTDA标记物，并做了一系列小鼠动物分布实验，证明99mTcO-MPTDA具有一定的脑摄取，尤其是当加入溴离子参与标记反应时，初始脑摄取达到了99mTcO-MPBDA的水平。四种配合物的脑滞留性质都非常好，最差的碘离子配合物的相对滞留率R都在70%以上。测定了99mTcO- MPDAA和99mTcO-MPBDA、99mTcO-MPTDA的脂水分配系数和电荷性质。进行了小鼠动物分布实验，证明99mTcO-MPDAA具有一定的脑摄取，初始脑摄取略低于99mTcO-MPBDA的水平，在15min之后脑摄取超过了99mTcO-MPBDA。但由于血中摄取也很高，导致脑血比较低，所以作为理想的脑灌注显像剂的前景不如99mTcO-MPBDA好。对三种NNS三齿配体MPBDA、MPTDA、MPDAA进行了羰基锝核标记。通过各种条件实验优化其标记条件，确定了标记率大于90%的标记条件。在此基础上进行了小鼠体内分布实验。结果表明，三种标记化合物在小鼠血液和各组织器官内清除速度都比较快，各个主要脏器都有一定的摄取，但是除了在肝中有累积外，其他脏器没有明显的滞留。利用空间堆积模型，研究了99mTc脑显像剂在脑中滞留的性质与SAS值之间的关系。首次提出，脑显像剂要具有好的滞留性质，其SAS值要在0.906～0.915的范围之内，以此为指标设计的四种99mTc“3+1”配合物MPBDA-F、MPBDA-Cl、MPBDA-Br、MPBDA-I均有良好的滞留性质。事实证明，SAS值在0.906～0.915之间作为99mTc配合物具有良好的脑滞留性质的重要指标，是完全可靠的。这也是脑药物设计中第一次提出脑滞留性质的定量指标。

99mTc-d,l-HMPAO and 99mTcO-L,L-ECD are two kinds of brain perfusion imaging agents most widely used in clinic. But each one has its disadvantages. Furthermore, domestic radiopharmaceuticals are still in the phase of modeled on foreign pharmaceuticals. So the most urgent affair is to develop 99mTc radio pharmaceuticals with our own intellectual property rights whose characters are equal to advanced levels abroad.Based on participating in the research of 99mTcO-MPBDA, further works were done to perfect the preparations for clinical research. After series improvements on labeling methods and biodistribution experiments, human being imaging experiment, we found that γ-cyclodextrin used as solubility promoter could increase brain uptake to 34.6% higher and brain/blood ratio to 2 times. 99mTcO-MPBDA-Br was prepared with Br- as monodentate ligand and γ-cyclodextrin used as solubility promoter. Biodistribution in mice showed that brain uptake and brain/blood ratio are all beyond the 99mTcO-MPBDA-Cl prepared by old labeling method. The result of CBF(cerebral blood flow) measuring on a healthy adult female macaque as animal model demonstrated that 99mTcO-MPBDA could determine CBF exactly. In volunteer SPECT research, the results of brain perfusion imaging were good and could be used in clinical diagnosis. The stability in vitro of 99mTcO-MPBDA are better than that of 99mTc-d,l-HMPAO, and brain retention ability is better than 99mTcO-L,L-ECD, there still are brain uptake 3.45%ID/brain at 70min post-injection (p.i.). Although the beginning brain uptake is a little lower than that of 99mTcO-L,L-ECD, but it overcomes the defect that results of 99mTcO-L,L-ECD was effected by enzyme distribution because the retention mechanism is enzyme hydrolyzed, and the intellectual property rights are whole owned by ourselves. So 99mTcO-MPBDA could be declared for new medicine as a kind of brain imaging agent.Kit of 99mTcO-MPBDA was prepared after a set of conditions experiments. Labeling yield of the kit is still higher than 95% although it has been stored in room for two weeks. And the results of biodistribution experiments in mice showed that mannitol draw in the procedure of kit formulation not only didn’t changed the good brain uptake and retention, but also accelerated the rapid cleared from blood then made the brain/blood ratio raised sharply follow the time which is very beneficial to brain imaging. The kit absolutely can be used for clinical research.Two new tridentate ligands MPTDA and MPDAA were synthesized and characterized by IR, 1H-NMR and MS analysis. The preparations have not been reported in literature. 99mTcO-MPTDA and 99mTcO-MPDAA were prepared and factors affecting labeling yield were also studied, labeling yield was raised to higher than 95%. Then different 99mTcO-MPTDA labeled products were prepared by added different halide anions and a set of biodistribution experiments in mice were done. Results showed that 99mTcO-MPTDA had certainly brain uptake, especially when Br- was added the beginning brain uptake of 99mTcO-MPTDA reached the level of 99mTcO-MPBDA. 99mTcO-MPTDA labeled with F-, Cl-, Br-, I- added all had good brain retention abilities. The lowest R-value in the 4 99mTcO-MPTDA-X is still more than 70%. Apparent partition coefficient and charge of 99mTcO-MPDAA, 99mTcO-MPBDA and 99mTcO-MPTDA were determined. Biodistribution experiments in mice showed that 99mTcO-MPDAA had certain brain uptake, at beginning the value was a little lower than that of 99mTcO-MPBDA, but it became higher than 99mTcO-MPBDA 15min p. i. . But the blood uptake was also higher so the brain/blood ratio was not too high. So potential of 99mTcO-MPDAA used as brain imaging agent is not as good as 99mTcO-MPBDA.[99mTc(CO)3-core] complexes were prepared by ligand-exchange reaction with [99mTc(CO)3(H2O)3]+ and MPBDA、MPTDA、MPDAA. And factors affecting labeling yield were also studied, preparing procedure was decided which could ensured labeling yield higher than 90%. Biodistribution experiments in mice showed that [99mTc(CO)3-MPBDA], [99mTc(CO)3-MPTDA] and [99mTc(CO)3- MPDAA] rapidly clear from blood and other organs. There were certain uptake in main tissue and organs, but except accumulated in liver, no obviously retention could be seen in other organs.The relationship between SAS value and brain retention ability of 99mTc brain imaging agents was studied using space-packing model. We indicate the first time that brain imaging agent had good retention ability request its SAS value was between 0.906~0.915. Using this indicator to design 4 kind of 99mTc“3+1”complexes MPBDA-F、MPBDA-Cl、MPBDA-Br、MPBDA-I, then the results of biodistribution experiments in mice all showed good brain retention. The factors demonstrated that SAS value between 0.906~0.915 as important indicator of brain imaging agent with good brain retention ability is absolutely reliable. In brain medicine design this is the first time to bring up quantitative indicator of brain retention ability.