Use of LC/MS to assess brain tracer distribution in preclinical, in vivo receptor occupancy studies: Dopamine D2, serotonin 2A and NK-1 receptors as examples

Autor: Vanessa N. Barth, Laura J. Martin, Karen S. Rash, Eyassu Chernet, Dominic L. Li, Lee A. Phebus, Anne B. Need
Rok vydání: 2005
Předmět:
Male
medicine.medical_specialty
Morpholines
Drug Evaluation
Preclinical
Tetrazoles
Pharmacology
Mass Spectrometry
General Biochemistry
Genetics and Molecular Biology
Benzodiazepines
Neurokinin-1 Receptor Antagonists
Piperidines
Dopamine
In vivo
Dopamine receptor D2
Internal medicine
Serotonin 5-HT2 Receptor Antagonists
medicine
Haloperidol
Animals
Receptor
Serotonin
5-HT2A
General Pharmacology
Toxicology and Pharmaceutics
Receptor
Clozapine
Chromatography
High Pressure Liquid
Raclopride
Dose-Response Relationship
Drug
Receptors
Dopamine D2
Chemistry
Drug Administration Routes
Brain
General Medicine
Receptors
Neurokinin-1
Rats
Fluorobenzenes
Dopamine D2 Receptor Antagonists
Endocrinology
Olanzapine
Dopamine Antagonists
Serotonin Antagonists
Serotonin
Gerbillinae
Aprepitant
Antipsychotic Agents
medicine.drug
Zdroj: Life Sciences. 78:340-346
ISSN: 0024-3205
DOI: 10.1016/j.lfs.2005.04.075
Popis: High performance liquid chromatography combined with either single quad or triple quad mass spectral detectors (LC/MS) was used to measure the brain distribution of receptor occupancy tracers targeting dopamine D2, serotonin 5-HT2A and neurokinin NK-1 receptors using the ligands raclopride, MDL-100907 and GR205171, respectively. All three non-radiolabeled tracer molecules were easily detectable in discrete rat brain areas after intravenous doses of 3, 3 and 30 microg/kg, respectively. These levels showed a differential brain distribution caused by differences in receptor density, as demonstrated by the observation that pretreatment with compounds that occupy these receptors reduced this differential distribution in a dose-dependent manner. Intravenous, subcutaneous and oral dose-occupancy curves were generated for haloperidol at the dopamine D2 receptor as were oral curves for the antipsychotic drugs olanzapine and clozapine. In vivo dose-occupancy curves were also generated for orally administered clozapine, olanzapine and haloperidol at the cortical 5-HT2A binding site. In vivo occupancy at the striatal neurokinin NK-1 binding site by various doses of orally administered MK-869 was also measured. Our results demonstrate the utility of LC/MS to quantify tracer distribution in preclinical brain receptor occupancy studies.
Databáze: OpenAIRE
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