Development of fluorinated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogs with potent nigrostriatal toxicity for potential use in positron emission tomography studies.

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.