多巴胺转运蛋白显像剂^(99)Tc^m-TRODAT-1临床前药理研究

Preclinical pharmacological studies of ^(99)Tc^m-TRODAT-1 as a dopamine transporter imaging agent

目的 研究多巴胺转运蛋白 (DAT)显像剂99Tcm 2 β [N ,N’ 双 (2 巯乙基 )乙撑二胺基 ]甲基 ,3β (4 氯苯基 )托烷 (TRODAT 1)用于帕金森病 (PD)早期诊断的价值。 方法 制备99Tcm TRODAT 1,用 2 β 羧甲基 ,3β (4 碘苯基 )托烷 (β CIT)阻断DAT后 ,观察大鼠脑内分布、兔血药清除动力学、异常毒性实验、正常及PD模型鼠的放射自显影图并对志愿者进行显像。结果 制备的99Tcm TRODAT 1放化纯大于 90 % ,室温下放置 6h稳定 ;用 β CIT阻断后大鼠纹状体的特异性摄取即纹状体与小脑放射性计数差除以小脑放射性计数为 0 .12 (对照组为 3.45 ) ,表明 β CIT对99Tcm TRODAT 1有明显的竞争抑制作用。血药清除动力学研究表明它的分布半衰期T1/2 (α) =1.2min ,消除半衰期T1/2 (β) =36 8min。模型鼠的放射自显影结果表明纹状体的特异摄取随着给药 (神经毒素 )总量的增加而减少 ,并有良好的线性关系 (r =- 0 .9792 )。正常猴断层显像在 3个断面上基底节均有明显高于周围组织的摄取 ,单侧PD模型猴显像示健侧纹状体与小脑的比值 (1.5 6 )明显高于损毁侧比值 (0 .94)。志愿者脑断层图像清晰 ,患侧纹状体对99Tcm TRODAT 1摄取较正常侧减低 ,其显像结果分析与临床表现相吻合。结论 99Tcm TRODAT 1制备方便 。

Objective To develop a 99 Tc m labeled dopamine transporter (DAT) imaging agent, 99 Tc m TRODAT 1 [TRODAT 1: 2β ([ N,N' bis(2 mercaptoethyl) ethylenediamino] methyl),3β (4 chlorophenyl)tropane], for evaluating the variation of DAT in patients with Parkinson's disease. Methods 99 Tc m TRODAT 1 was successfully prepared on a kit basis. Preclinical pharmacological studies were performed in rats, mice, rabbits,monkeys and a volunteer with diagnosed Parkinson disease (PD). Results Radiochemical purity of 99 Tc m TRODAT 1 was over 90%, and remained stable for 6 hours. The specific uptake in striatum was significantly diminished, from 3.45 to 0.12 at 2 h by pretreating rats with a dose of DAT competing ligand, β CIT [1 mg/kg, 2β carbomethoxy 3β (4 iodophenyl)tropane]. Blood clearance kinetics was studied in rabbits, and the initial half life was of 1.2 min, the elimination half life was of 368 min. Images of normal monkey's brain exhibited an excellent accumulation in basal ganglia region, where dopamine neurons were concentrated. In hemiparkinsonism model monkeys, the ratio of normal ST/CB and lessioned ST/CB were 1.56 and 0.94, respectively. Brain imaging studies in volunteer indicated that uptake and retention in the basal ganglia, the ratio of normal striatal uptake to lessioned one's was 1.15 measured by SPECT imaging at 2 h. The result of imaging was conformrable with his clinical symptoms. Conclusions The stable, neutral and lipophilic complex, 99 Tc m TRODAT 1, can be accumulated in the striatal area, where DAT is concentrated, high quality images can be obtained. It suggests that 99 Tc m TRODAT 1 might be a safe and effective tracer for monitoring the variation in DAT which is associated with various neurodegenerative diseases.