Flexible N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine analogues: synthesis and monoamine oxidase catalyzed bioactivation.

Eighteen analogues of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were synthesized and evaluated as substrates of monoamine oxidase. In general, the flexible analogues, characterized by the presence of a methylene (or ethylene) bridge between the aryl/heteroaryl and tetrahydropyridyl moieties, were better substrates of the enzyme than the conformationally restricted MPTP. It is suggested that the increased oxidative activity of these flexible analogues reflects enhanced binding due to the ability of the C-4-aryl/heteroaryl substituent to gain access to a hydrophobic pocket within the substrate binding site.

Pargyline-sensitive selective accumulation of a radiolabeled MPTP analog in the primate cerebral cortex and basal ganglia.

The distribution of radioiodinated N-methyl-4-(4-hydroxy-3-iodobenzyl)-1,2,3,6-tetrahydropyridine (MHTP), an analog of the reportedly nontoxic N-methyl-4-benzyl-1,2,3,6-tetrahydropyridine, (4-homo-MPTP), has been studied in the primate. [123I]MHTP-derived radioactivity exhibited a progressive accumulation and prolonged retention within the primate eye. Following iv injection, [123I]MHTP rapidly accumulated within the primate brain and was subsequently oxidized to a radiolabeled metabolite. The half-life of [123I]MHTP-derived radioactivity within the primate brain was 50 min. The highest concentrations of radioactivity were found in the caudate-putamen and the frontal, temporal and cingulate cortices; the substantia nigra and inferior olivary nucleus were labeled with medium intensity. Very low concentrations of radiolabel were detected in the cerebellum and white matter. Selective accumulation of [125I]MHTP-derived radioactivity within these structures was blocked by pretreatment with pargyline, suggesting that monoamine oxidase B is involved in the bioactivation of radioiodinated MHTP.