[18F]Fluoro-beta-fluoromethylene-m-tyrosine derivatives show stereo, geometrical, and regio specificities as in vivo central dopaminergic probes in monkeys.
Stereo (D and L), geometrical (E and Z), and regiospecific (2-, 4-, and 6-[18F]fluoro) analogs of beta-fluoromethylene-m-tyrosine (FMMT) have been investigated in adult vervet monkeys (Cercopithecus aethiops sabaeus, n = 12) in vivo with positron emission tomography (PET). Brain transport through the blood-brain barrier and central aromatic amino acid decarboxylase (AAAD)-mediated decarboxylation rates were established. Results show strict structural dependency of the kinetic behavior of radiofluorinated FMMT analogs, with the E-isomer exhibiting a higher specificity over the (Z) geometrical counterpart for central dopaminergic structures. The 6-[18F]fluoro substituted L-(E)-FMMT was also favored over the 2- and 4-[18F]fluorosubstituted isomers in terms of their ability to localize in the same brain areas. The role of PET in drug development is also exemplified in this work.
Huang
S C
SC
Department of Molecular and Medical Pharmacology, UCLA School of Medicine, Los Angeles, California 90095, USA.
Quintana
J
J
Satyamurthy
N
N
Lacan
G
G
Yu
D C
DC
Phelps
M E
ME
Barrio
J R
JR
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004298:Dopamine / Q000502:physiology*; D005462:Fluorine Radioisotopes; D008996:Monoamine Oxidase Inhibitors / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014055:Tomography, Emission-Computed; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D005462:Fluorine Radioisotopes; D008996:Monoamine Oxidase Inhibitors; D014443:Tyrosine; C046880:beta-fluoromethylene-3-tyrosine; D004298:Dopamine