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) t oxicity stimulated intense interest in neurotoxicology and in the poss ible toxic etiology of Parkinson's disease. Better understanding of MP TP neurotoxicity may be achieved by studies using F-18-radiolabeled MP TP analogs and positron emission tomography in nonhuman primates. We s ynthesized three fluorinated analogs of MPTP: thyl-4-(2-fluorophenyl)- 1,2,3,6-tetrahydropyridine (2'-F-MPTP), rifluorome-thyl)phenyl]-1,2,3, 6-tetrahydropyridine (2'-CF3-MPTP) and 2-(fluoromethyl)phenyl]-1,2,3,6 -tetrahydropyridine (2'-CH2F-MPTP), and developed a method for prepari ng the latter in F-18-labeled form. We now studied the suitability of 2'-CH2F-MPTP and its hydrolysis products as substrates for monoamine o xidase (MAO) from mouse and monkey brain preparations, and investigate d the neurotoxic effect of 2'-CH2F-MPTP and 2'-F-MPTP on the nigrostri atal dopaminergic system in mice. We found that 2'-CH2F-MPTP is a bett er substrate for MAO and that both 2'-CH2F-MPTP and 2'-F-MPTP were mor e potent neurotoxins than MPTP. Like MPTP, 2'-F-MPTP was exclusively o xidized 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, clorgylin e or deprenyl when given separately, but required clorgyline and depre nyl together.