Harik S I, Riachi N J, Hritz M A, Berridge M S, Sayre L M
Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
J Pharmacol Exp Ther. 1993 Aug;266(2):790-5.
The discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity stimulated intense interest in neurotoxicology and in the possible toxic etiology of Parkinson's disease. Better understanding of MPTP neurotoxicity may be achieved by studies using 18F-radiolabeled MPTP analogs and positron emission tomography in nonhuman primates. We synthesized three fluorinated analogs of MPTP: 1-methyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine (2'-F-MPTP), 1-methyl-4-[2-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-CF3-MPTP) and 1-methyl-4-[2-(fluoromethyl)phenyl]-1,2,3,6-tetrahydropyridine (2'-CH2F-MPTP), and developed a method for preparing the latter in 18F-labeled form. We now studied the suitability of 2'-CH2F-MPTP and its hydrolysis products as substrates for monoamine oxidase (MAO) from mouse and monkey brain preparations, and investigated the neurotoxic effect of 2'-CH2F-MPTP and 2'-F-MPTP on the nigrostriatal dopaminergic system in mice. We found that 2'-CH2F-MPTP is a better substrate for MAO and that both 2'-CH2F-MPTP and 2'-F-MPTP were more potent neurotoxins than MPTP. Like MPTP, 2'-F-MPTP was exclusively oxidized by MAO-B and its toxicity blocked by pargyline or deprenyl but not by clorgyline. In contrast, 2'-CH2F-MPTP was oxidized by both MAO-A and MAO-B, and its toxicity was not blocked by pargyline, clorgyline or deprenyl when given separately, but required clorgyline and deprenyl together.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）毒性的发现激发了人们对神经毒理学以及帕金森病可能的毒性病因的浓厚兴趣。通过在非人类灵长类动物中使用18F放射性标记的MPTP类似物和正电子发射断层扫描进行研究，可能会更好地理解MPTP神经毒性。我们合成了三种MPTP的氟化类似物：1-甲基-4-（2-氟苯基）-1,2,3,6-四氢吡啶（2'-F-MPTP）、1-甲基-4-[2-（三氟甲基）苯基]-1,2,3,6-四氢吡啶（2'-CF3-MPTP）和1-甲基-4-[2-（氟甲基）苯基]-1,2,3,6-四氢吡啶（2'-CH2F-MPTP），并开发了一种制备18F标记形式的后者的方法。我们现在研究了2'-CH2F-MPTP及其水解产物作为小鼠和猴脑制剂中单胺氧化酶（MAO）底物的适用性，并研究了2'-CH2F-MPTP和2'-F-MPTP对小鼠黑质纹状体多巴胺能系统的神经毒性作用。我们发现2'-CH2F-MPTP是MAO更好的底物，并且2'-CH2F-MPTP和2'-F-MPTP都是比MPTP更强效的神经毒素。与MPTP一样，2'-F-MPTP仅被MAO-B氧化，其毒性被帕吉林或司来吉兰阻断，但不被氯吉兰阻断。相比之下，2'-CH2F-MPTP被MAO-A和MAO-B两者氧化，并且当单独给药时其毒性不被帕吉林、氯吉兰或司来吉兰阻断，但需要氯吉兰和司来吉兰一起使用。
