Design and synthesis of 18F-labeled neurotoxic analogs of MPTP

Abstract

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