title: Potent neurotoxic fluorinated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs as potential probes in models of Parkinson disease.
abstract: We synthesized a number of fluorinated analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and tested their suitability as substrates for monoamine oxidase B in vitro and their dopaminergic neurotoxicity in vivo. Two of the compounds tested, 2'-F-MPTP and 2'-CF3-MPTP, were better enzyme substrates and possessed more potent neurotoxicity for nigrostriatal dopamine neurons than MPTP, especially 2'-F-MPTP. The results of the in vivo neurotoxicity experiments correlated well with the suitability of the compounds as substrates for monoamine oxidase. These findings could serve as a basis for the use of 18F-labeled analogs of MPTP for positron emission tomography studies of nonhuman primates for better understanding of the factors underlying MPTP toxicity. Furthermore, the discovery of two MPTP analogs with enhanced selective neurotoxicity to dopaminergic neurons may be an important clue in the continuing efforts to define the chemical structure-activity factors governing MPTP neurotoxic activation mechanisms.
authors.affiliation: Department of Neurology, Case Western Reserve University, Cleveland, Ohio 44106.
authors.forename: N J
authors.initials: NJ
authors.lastname: Riachi
authors.forename: P K
authors.initials: PK
authors.lastname: Arora
authors.forename: L M
authors.initials: LM
authors.lastname: Sayre
authors.forename: S I
authors.initials: SI
authors.lastname: Harik
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology; D008995:Monoamine Oxidase / Q000378:metabolism*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced*; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D011725:Pyridines; C055227:3'-trifluoro-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C055226:2'-fluoro-N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase