DESIGN AND SYNTHESIS OF F-18 LABELED NEUROTOXIC ANALOGS OF MPTP

We report on the synthesis of two fluorine-18 labeled analogs of 1-met hyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A piperidyl triazene w as fluorinated to produce thyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropy ridine (2'-F-MPTP, 12) in very low yield, and 2-(fluoromethyl)phenyl]- 1,2,3,6-tetrahydropyridine (2'-FCH2-MPTP, 11) was labeled with F-18 by nucleophilic displacement of the corresponding chloride in 60% yield. The biodistribution in mice of the latter radiotracer and its oxidati on to 1-methyl-4-[2-(fluoromethyl)phenyl]pyridinium (2'-FCH2-MPP+, 6) is also reported. The kinetics of oxidation of 2'-FCH2-MPTP and its so lvolysis products (the corresponding 2'-hydroxymethyl and 2'-chloromet hyl analogs) by rat liver monoamine oxidase were investigated. 2'-FCH2 -MPTP accumulated to a useful degree in the brain, was oxidized by mon oamine oxidase in vitro, was converted to the oxidation product in bra in in vivo, and had a neurotoxic potency similar to that of MPTP. We f eel it may be useful as an F-18-labeled radiopharmaceutical for positr on tomographic studies of the mechanisms of MPTP toxicity.