Meegalla S K, Plössl K, Kung M P, Chumpradit S, Stevenson D A, Kushner S A, McElgin W T, Mozley P D, Kung H F
Department of Radiology, University of Pennsylvania, Philadelphia 19104, USA.
J Med Chem. 1997 Jan 3;40(1):9-17. doi: 10.1021/jm960532j.
In the development of novel Tc-99m-labeled tropane derivatives as dopamine transporter (reuptake site)-imaging agents, a series of neutral and lipophilic complexes containing bis-(aminoethanethiol) as a neutral complexing moiety for a [99mTc]TcO3+ center core was successfully prepared. Biological evaluation of the Tc-99m-labeled complexes 13-16 as central nervous system (CNS) dopamine transporter-imaging agents was reported. Synthesis of the tropane derivatives was achieved by stepwise reactions adding two aminoethanethiol units. The final free thiol ligands were obtained by deblocking the 4-methoxybenzyl protecting group with Hg(OAc)2 to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of 16, displayed good initial brain uptake and selective uptake in the striatal area, where dopamine transporters are concentrated. One of the compounds, [2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo [3.2.1]oct-2-yl]methyl](2-mercaptoethyl)amino]ethy] amino]ethanethiolato-(3-)-N2,N2',S2,S2'] oxo-[1R-(exo-exo)]- [99mTc]technetium,[99mTc]TRODAT-1 (13), displayed the highest initial uptake in rat brain (0.4% at 2 min post iv injection); the striatal/cerebellar (ST/ CB) ratio reached 2.8 at 60 min after an iv injection. The specific uptake in rat brain can be blocked by pretreating rats with a competing dopamine transporter binding agent, beta-CIT (RTI-55, 2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane; iv, 1 mg/kg), which reduced the regional brain uptake ratio (ST/CB) to 1.2. In contrast, the specific striatal uptake was not affected by pretreating rats with a noncompeting ligand, haldol (iv, 1 mg/kg). After an iv injection of 9 mCi of [99mTc]TRODAT-1 (13), in vivo images of baboon brain using single-photon emission-computed tomography exhibited excellent localization in striatum (basal ganglia), where dopamine neurons are known to be concentrated. This series of compounds may provide a convenient source of short-lived imaging agents for routine diagnosis of CNS diseases (i.e., Parkinson's disease) in which changes in the dopamine transporter concentration are implicated.
在开发新型锝-99m标记的托烷衍生物作为多巴胺转运体（再摄取位点）显像剂的过程中，成功制备了一系列含有双（氨基乙硫醇）作为[99mTc]TcO3+中心核中性络合部分的中性亲脂性络合物。报道了对锝-99m标记的络合物13 - 16作为中枢神经系统（CNS）多巴胺转运体显像剂的生物学评价。托烷衍生物的合成通过逐步添加两个氨基乙硫醇单元的反应来实现。最终的游离硫醇配体通过用Hg(OAc)2去除4 - 甲氧基苄基保护基得到三氟乙酸盐。除了16之外，所有的锝-99m络合物在脑内均表现出良好的初始摄取以及在纹状体区域的选择性摄取，多巴胺转运体在该区域高度集中。其中一种化合物，[2 - [[2 - [[[3 - (4 - 氯苯基)-8 - 甲基-8 - 氮杂双环[3.2.1]辛-2 - 基]甲基](2 - 巯基乙基)氨基]乙基]氨基]乙硫醇根合-(3 - )-N2,N2',S2,S2']氧代-[1R-(外-外)]-[99mTc]锝，[99mTc]TRODAT - 1（13），在大鼠脑内的初始摄取量最高（静脉注射后2分钟时为0.4%）；静脉注射后60分钟时纹状体/小脑（ST/CB）比值达到2.8。大鼠脑内的特异性摄取可通过用竞争性多巴胺转运体结合剂β - CIT（RTI - 55，2β - 甲氧羰基-3β-(4 - 碘苯基)托烷；静脉注射，1 mg/kg）预处理大鼠来阻断，这使得脑区摄取比值（ST/CB）降至1.2。相反，用非竞争性配体氟哌啶醇（静脉注射，1 mg/kg）预处理大鼠并不影响纹状体的特异性摄取。静脉注射9 mCi的[99mTc]TRODAT - 1（13）后，使用单光子发射计算机断层扫描对狒狒脑进行的体内成像显示在纹状体（基底神经节）中有出色的定位，已知多巴胺神经元在该区域集中。这一系列化合物可能为常规诊断涉及多巴胺转运体浓度变化的中枢神经系统疾病（即帕金森病）提供一种方便的短寿命显像剂来源。
