Design and synthesis of 18F-labeled neurotoxic analogs of MPTP.
We report on the synthesis of two fluorine-18 labeled analogs of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). A piperidyl triazene was fluorinated to produce [18F]-1-methyl-4-(2-fluorophenyl)-1,2,3,6-tetrahydropyridine (2'-F-MPTP, 12) in very low yield, and 1-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 1-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.
Berridge
M S
MS
Department of Radiology, Case Western Reserve University, Cleveland, Ohio 44106.
Sayre
L M
LM
Arora
P K
PK
Terris
A H
AH
Riachi
N J
NJ
Harik
S I
SI
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D005462:Fluorine Radioisotopes; D006868:Hydrolysis; D007553:Isotope Labeling; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D020267:MPTP Poisoning; D008297:Male; D051379:Mice; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D009422:Nervous System Diseases / Q000139:chemically induced*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
C081118:1-methyl-4-(2-(fluoromethyl)phenyl)-1,2,3,6-tetrahydropyridine; D005462:Fluorine Radioisotopes; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase