RÉSUMÉ
Methylphenidate (MPH) is a psychostimulant approved by the FDA to treatment Attention-Deficit Hyperactivity Disorder (ADHD). MPH is believed to exert its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. We used a quantitative non-invasive PET imaging technique to study the effects of long-term methylphenidate use on the central nervous system (CNS). We conducted microPET/CT scans on young adult male rhesus monkeys to monitor changes in the dopaminergic system. We used [18F] AV-133, a ligand for the vesicular monoamine transporter 2 (VMAT2), and [18F]FESP a ligand for the D2 and 5HT2 receptors. In this study we evaluated the effects if chronic MPH treatment in the nonhuman primates (NHP). Two-year-old, male rhesus monkeys were orally administered MPH diluted in the electrolyte replenisher, Prang, twice a day, five days per week (M-F) over an 8-year period. The dose of MPH was gradually escalated from 0.15 mg/kg initially to 2.5 mg/kg/dose for the low dose group, and 1.5 mg/kg to 12.5 mg/kg/dose for the high dose group (Rodriguez et al., 2010). Scans were performed on Mondays, about 60 h after their last treatment, to avoid the acute effects of MPH. Tracers were injected intravenously ten minutes before microPET/CT scanning. Sessions lasted about 120 min. The Logan reference tissue model was used to determine the Binding Potential (BP) of each tracer in the striatum with the cerebellar cortex time activity curve as an input function. Both MP treatment groups had a lower [18F] AV-133 BP, although this failed to reach statistical significance. MPH treatment did not have a significant effect on The BP of [18F] FESP in the striatum. Long-term administration of MPH did not significant change any of the marker of monoamine function used here. These data suggest that, despite lingering concerns, long-term use of methylphenidate does not negatively impact monoamine function. This study also demonstrates that microPET imaging can distinguish differences in binding potentials of a variety of radiotracers in the CNS of NHPs. This approach may provide minimally-invasive biomarkers of neurochemical processes associated with chronic exposure to CNS medications. (Supported by NCTR).
Sujet(s)
Encéphale/effets des médicaments et des substances chimiques , Transporteurs de la dopamine/effets des médicaments et des substances chimiques , Méthylphénidate/pharmacologie , Facteurs temps , Animaux , Stimulants du système nerveux central/administration et posologie , Stimulants du système nerveux central/pharmacologie , Dopamine/métabolisme , Transporteurs de la dopamine/métabolisme , Macaca mulatta , Méthylphénidate/administration et posologie , Transporteurs de la norépinéphrine/métabolisme , Transporteurs de la norépinéphrine/pharmacologie , Tomographie par émission de positons/méthodes , Tomodensitométrie/méthodes , Transporteurs vésiculaires des monoamines/effets des médicaments et des substances chimiques , Transporteurs vésiculaires des monoamines/métabolismeRÉSUMÉ
Our previous study indicated that a chiral compound 071031B was a novel serotonin and noradrenaline reuptake inhibitor with superior antidepressant activity compared to duloxetine. The present study aimed to investigate chiral pharmacology differences of 071031B enantiomers, S-071031B and R-071031B, and disclose mechanisms underlying the behavioral differences based on target profiles and pharmacokinetic profiles. In vivo behavioral tests indicated that S-071031B was more potent than R-071031B in two depression models (the forced swimming test in mice and rats) and two pain models (the acetic acid-induced writhing and formalin tests in mice). In vitro assays revealed that both S-071031B and R-071031B showed high affinity for human serotonin transporters and norepinephrine transporters with equal potency, and showed consistently equipotent inhibitory effects on serotonin and norepinephrine uptake. Pharmacokinetic studies demonstrated that oral availability and hepatic metabolism, rather than pH stability, intestinal transport, and plasma binding, contributed to enantiomers' behavioral differences. Based on these findings, it is suggested that S-071031B is a more active enantiomer, and the differential pharmacokinetic profiles, but not target affinity, contribute to differences of S-071031B and R-071031B in behavioral pharmacology. Moreover, current PK-PD study may provide positive exploration for chiral antidepressants development.
Sujet(s)
Benzodioxoles/pharmacologie , Benzodioxoles/pharmacocinétique , Inhibiteurs de la recapture de la sérotonine et de la noradrénaline/pharmacologie , Inhibiteurs de la recapture de la sérotonine et de la noradrénaline/pharmacocinétique , Sérotonine/métabolisme , Thiophènes/pharmacologie , Thiophènes/pharmacocinétique , Animaux , Antidépresseurs/pharmacocinétique , Antidépresseurs/pharmacologie , Comportement animal/effets des médicaments et des substances chimiques , Dépression/traitement médicamenteux , Dépression/métabolisme , Trouble dépressif/traitement médicamenteux , Trouble dépressif/métabolisme , Chlorhydrate de duloxétine/pharmacocinétique , Chlorhydrate de duloxétine/pharmacologie , Mâle , Souris , Souris de lignée ICR , Norépinéphrine/métabolisme , Transporteurs de la norépinéphrine/pharmacocinétique , Transporteurs de la norépinéphrine/pharmacologie , Rats , Rat Sprague-Dawley , Transporteurs de la sérotonine/métabolisme , Natation/physiologieRÉSUMÉ
The synthesis and SAR of a series of chiral heterocyclic ring-constrained norepinephrine reuptake inhibitors are described. The best compounds compare favorably with atomoxetine in potency (IC(50)s<10 nM), selectivity against the other monoamine transporters, and inhibition of CYP2D6 (IC(50)s>1 microM). In addition, the compounds are generally more stable than atomoxetine to oxidative metabolism and thus are likely to have lower clearance in humans.
Sujet(s)
Inhibiteurs de la capture adrénergique/synthèse chimique , Inhibiteurs de la capture adrénergique/pharmacologie , Chimie pharmaceutique/méthodes , Transporteurs de la norépinéphrine/synthèse chimique , Transporteurs de la norépinéphrine/pharmacologie , Norépinéphrine/composition chimique , Oxygène/composition chimique , Inhibiteurs de la capture adrénergique/composition chimique , Chlorhydrate d'atomoxétine , Cytochrome P-450 CYP2D6/composition chimique , Conception de médicament , Humains , Concentration inhibitrice 50 , Modèles chimiques , Conformation moléculaire , Norépinéphrine/métabolisme , Propylamines/composition chimique , Propylamines/pharmacologie , Relation structure-activité , Symporteurs/composition chimiqueRÉSUMÉ
The design, synthesis, and SAR of a series of ring-constrained norepinephrine reuptake inhibitors are described. A substantially rigid inhibitor with potent functional activity at the transporter (IC(50)=8 nM) was used to develop a model for the distance and orientation of key features necessary for interaction with the norepinephrine transporter (NET).