Synthesis and characterization of technetium-99m-labeled tropanes as dopamine transporter-imaging agents.
Synthesis and characterization of technetium-99m-labeled tropanes as dopamine transporter-imaging agents.
复制标题
作为多巴胺转运蛋白成像剂的锝-99m 标记托烷的合成和表征。
DOI：
10.1021/jm960532j
复制
发表时间：
1997
期刊：
影响因子：
--
通讯作者：
Kung,HF
中科院分区：
文献类型：
--
作者：
Meegalla,SK;Plossl,K;Kung,MP;Chumpradit,S;Stevenson,DA;Kushner,SA;McElgin,WT;Mozley,PD;Kung,HF
在开发新的Tc-99 m-labeled tropane衍生物作为多巴胺转运蛋白（再摄取位点）显像剂，一系列的中性和亲脂性的配合物含有双（氨基乙烷）作为一个中性络合部分的[99 mTc] TcO 3+中心核成功地制备。报道了Tc-99 m标记的络合物13 − 16作为中枢神经系统（CNS）多巴胺转运蛋白显像剂的生物学评价。通过加入两个氨基乙烷乙氧基单元的分步反应合成了托烷衍生物。通过用Hg（OAc）2将4-甲氧基苄基保护基去封闭以获得三氟乙酸盐来获得最终的游离硫醇配体。所有的Tc-99 m络合物，除了16，显示良好的初始脑摄取和选择性摄取纹状体区，多巴胺转运集中。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]乙硫醇合（3-）-N2，N2 '，S2，S2']氧代-[1 R-（exo-exo）]- [99 mTc]锝，[99 mTc]TRODAT-1（13）在大鼠脑中显示最高的初始摄取（静脉注射后2分钟为0.4%）;纹状体/小脑（ST/CB）比值在静脉注射后60分钟达到2.8。大鼠脑中的特异性摄取可通过用竞争性多巴胺转运蛋白结合剂β-CIT（RTI-55，2β-甲氧羰基-3 β-（4-碘苯基）托烷; iv，1 mg/kg）预处理大鼠来阻断，这将局部脑摄取比（ST/CB）降低至1.2。与此相反，特定的纹状体摄取不受预处理大鼠与非竞争性配体，氟哌啶醇（iv，1毫克/公斤）。静脉注射9 mCi的[99 mTc]TRODAT-1（13）后，使用单光子发射计算机断层扫描的狒狒大脑体内图像显示出纹状体（基底神经节）的良好定位，已知多巴胺神经元集中在纹状体。这一系列化合物可提供用于CNS疾病（即，帕金森氏病），其中涉及多巴胺转运蛋白浓度的变化。
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 complexes13−16as 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)2to obtain trifluoroacetate salts. All of the Tc-99m complexes, with the exception of16, 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]ethyl]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, β-CIT (RTI-55, 2β-carbomethoxy-3β-(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 vivoimages 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.