Meegalla S K, Plössl K, Kung M P, Stevenson D A, Mu M, Kushner S, Liable-Sands L M, Rheingold A L, Kung H F
Department of Radiology, University of Pennsylvania, Philadelphia 19716, USA.
J Med Chem. 1998 Feb 12;41(4):428-36. doi: 10.1021/jm970742b.
Recently, we reported the first human study of [99mTc]TRODAT-1, technetium, 2-[[2-[[[3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2- yl]methyl](2-mercaptoethyl)amino]ethyl]amino]-ethanethiolato(3-)-o xo- [1R-(exo-exo)]-, as an imaging agent of central nervous system (CNS) dopamine transporters. Due to the existence of several chiral centers on this molecule, upon the formation of [99mTc]TRODAT-1 complex (2) several diastereomers could be created. Two major diastereomers of [99mTc]TRODAT-1 (2), designated as peak A (2A) and peak B (2B), were separated by HPLC. Biodistribution of the purified diastereomers 2A,B was evaluated in rats. It appears that 2A displayed a higher lipophilicity than 2B (PC = 305 and 229, respectively), and a similar trend was observed for the initial brain uptake at 2 min postinjection (0.50% and 0.28% dose/organ for 2A,B, respectively). At 60 min post-iv-injection, the specific uptakes, as measured by [striatum - cerebellum]/cerebellum ([ST-CB]/CB) ratio, were 1.72 and 2.79 for 2A,B, respectively. The higher [ST-CB]/CB ratio observed for 2B was corroborated by the results of an in vitro binding assay. Higher binding affinity for dopamine transporters was observed for 3B (Ki = 13.87 and 8.42 nM for the analogous rhenium complexes 3A,B, respectively). The structure of the [99mTc]TRODAT-1 complexes was deduced using nonradioactive rhenium as a surrogate for radioactive technetium complex. Reacting free TRODAT-1 ligand with [Bu4N][ReOCl4] yielded two major complexes: Re-TRODAT-1A (3A) and Re-TRODAT-1B (3B) (corresponding with peaks A and B of [99mTc]TRODAT-1, respectively), whose structures were determined by X-ray analysis. The X-ray structures show that both complexes have a pseudo-square-pyramidal structure of [RevO]3+N2S2 core with oxygen occupying the apical position and the N-alkyl substitution in syn-configuration to the oxo-rhenium bond. In conclusion, TRODAT-1 formed at least two diastereomers after complexing with a metal(V)-oxo (M = 99mTc, Re) center core. The two isomers display different binding affinities toward dopamine transporters and distinct properties of localization in the striatum area of the brain where the transporters are located.
最近，我们报道了首例关于[99mTc]TRODAT-1（锝，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]-乙硫醇盐(3-)-氧代-[1R-(外向-外向)]-）作为中枢神经系统（CNS）多巴胺转运体显像剂的人体研究。由于该分子上存在多个手性中心，在形成[99mTc]TRODAT-1络合物（2）时可能会产生几种非对映异构体。通过高效液相色谱法分离出了[99mTc]TRODAT-1（2）的两种主要非对映异构体，分别命名为峰A（2A）和峰B（2B）。在大鼠中评估了纯化后的非对映异构体2A、2B的生物分布。似乎2A的亲脂性高于2B（分配系数分别为305和229），并且在注射后2分钟时的初始脑摄取也观察到类似趋势（2A、2B分别为0.50%和0.28%剂量/器官）。静脉注射后60分钟，通过[纹状体-小脑]/小脑（[ST-CB]/CB）比值测量的特异性摄取，2A、2B分别为1.72和2.79。体外结合试验的结果证实了2B观察到的较高[ST-CB]/CB比值。对于3B（类似的铼络合物3A、3B的抑制常数Ki分别为13.87和8.42 nM），观察到对多巴胺转运体具有更高的结合亲和力。使用非放射性铼作为放射性锝络合物的替代物推导了[99mTc]TRODAT-1络合物的结构。游离的TRODAT-1配体与[Bu4N][ReOCl4]反应产生了两种主要络合物：Re-TRODAT-1A（3A）和Re-TRODAT-1B（3B）（分别对应于[99mTc]TRODAT-1的峰A和峰B），其结构通过X射线分析确定。X射线结构表明，两种络合物都具有[RevO]3+N2S2核心的假四方锥结构，氧占据顶端位置，N-烷基取代与氧代铼键呈顺式构型。总之，TRODAT-1与金属（V）-氧代（M = 99mTc，Re）中心核心络合后形成了至少两种非对映异构体。这两种异构体对多巴胺转运体表现出不同的结合亲和力，并且在转运体所在的脑纹状体区域具有不同的定位特性。
