多巴胺转运蛋白显像剂^(99)Tc^m-TRODAT-1的制备及动物实验

Preparation and animal studies of 99 TcmTRODAT1 as a dopamine transporter imaging agent

目的研制早期诊断帕金森病的多巴胺转运蛋白（ＤＡＴ）显像剂９９Ｔｃｍ２β［Ｎ，Ｎ′双（２巯乙基）乙撑二胺基］甲基，３β（４氯苯基）托烷（ＴＲＯＤＡＴ１）。方法以可卡因为原料，经多步反应，合成配体ＴＲＯＤＡＴ１；用亚锡作还原剂，在葡庚糖酸钠（ＧＨ）存在下制备９９ＴｃｍＴＲＯＤＡＴ１。测定标记物的稳定性及在磷酸缓冲液和正辛醇中的分配系数，进行大鼠体内分布和猴显像实验。结果经ＩＲ、１ＨＮＭＲ、ＭＳ等鉴定，ＴＲＯＤＡＴ１与结构一致。制备的９９ＴｃｍＴＲＯＤＡＴ１经ＨＰＬＣ测定其放化纯＞９０％，室温下放置２４ｈ稳定；ｐＨ值７０和７４时的分配系数分别为１３２和１５４。大鼠体内分布结果：９９ＴｃｍＴＲＯＤＡＴ１在脑内浓聚较低（２、６０ｍｉｎ分别为０２８％和０１２％ＩＤ／ｏｒｇａｎ），但脑纹状体摄取２、３０、６０、１２０ｍｉｎ分别为０１９３％、０１８９％、０１４２％和０１３６％ＩＤ／ｇ，保留很好；而小脑、大脑皮质和海马清除较快，纹状体与小脑的比值随时间延长而升高（２、３０、６０、１２０ｍｉｎ分别为１０６、１７７、２４０和４４５），１２０ｍｉｎ纹状体与海马和大脑皮质的比值分?

Objective To develop 99 Tcm labeled dopamine transporter (DAT) imaging agent 99 Tcm(2 N,N bis(2mercaptoethyl) ethylenediamino]methyl, 3(4chlorophenyl)tropane (TRODAT1) for evaluating changes of DAT in patients with Parkinson's disease Methods TRODAT1 was synthesized from cocaine by stepwise reactions adding two aminoethanethiol units Using SnCl2 as reducing agent, and in the presence of Naglucoheptonate, 99 TcmTRODAT1 was prepared Animal studies have been performed in rats and normal monkeys Results The structure of TRODAT1 was confirmed by IR, 1 HNMR and MS Radiochemical purity of 99 TcmTRODAT1 was over 90%, and stable for 24 h at room temperature The partition coefficient in octanol and buffer was 132 and 154 at pH 70 and 74 respectively Biodistribution displayed relatively low uptake in rat brain (028 and 012%ID/organ at 2 min and 60 min post injection, respectively), but high uptake in liver (167%ID/organ at 60 min), steady uptake in kidney (maintained 3%ID/organ) The major radioactivity was excreted by hepatobiliary systems The distribution in rat's brain showed that striatal uptake were 0193, 0189, 0142 and 0136%ID/g at 2, 30, 60 and 120 min, respectively The ratios of striatal to cerebellar, striatal to hippocampal and striatal to cortical were 445 255 and 315 at 120 min post injection, respectively Brain image studies in monkeys indicated that TRODAT was uptaked and retained in the basal ganglia, where containing DAT abundantly Ratio of regional brain uptakes of striatum/cerebellum was 156 as measured by SPECT imaging at 120 min Conclusions Above results showed the stable, neutral and lipophilic complex 99TcmTRODAT1 can cross the blood brain barrier, and be selectively concentrated by the striatal area, where containing DAT abundantly High quality images of monkeys were also obtained It suggested that 99 TcmTRODAT1 may be a promising agent for clinical application