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Evaluation of [O-methyl-3H]WAY-100635 as an in vivo radioligand for 5-HT1A receptors in rat brain. 1994

S P Hume, and S Ashworth, and J Opacka-Juffry, and R G Ahier, and A A Lammertsma, and V W Pike, and I A Cliffe, and A Fletcher, and A C White
MRC Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.

N-(2-(4-(2-Methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) is a new, potent and selective 5-HT1A receptor antagonist. We have evaluated radiolabelled WAY-100635 as a prospective radioligand for positron emission tomography (PET) by studying biodistribution in rat ex vivo. After intravenous injection, [O-methyl-3H]WAY-100635 cleared rapidly from plasma but was retained in brain. Specific binding was quantified from kinetic studies, using a reference-tissue compartment model, fitting for binding potential (k3/k4). The regional variation in binding potential correlated with the known distribution of 5-HT1A receptors. Saturation studies gave Bmax values in vivo that were consistent with those reported in vitro. At 60 min after injection, the ratio of radioactivity in 5-HT1A receptor-rich regions (e.g. septum, entorhinal cortex and hippocampus) to that in cerebellum reached approximately 16. Pre-dosing the rats with WAY-100635 (2 mg/kg) reduced this ratio to one, whereas similar pre-dosing with citalopram (5-HT uptake site inhibitor), prazosin (alpha 1A-adrenoceptor antagonist) or idazoxan (alpha 2-adrenoceptor antagonist) caused little or no reduction. Substantial (77%) blockade of [3H]WAY-100635 binding was achieved with the 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), and the partial agonists, ipsapirone and buspirone. Thus, the properties of WAY-100635 are such that, when labelled with carbon-11, it could provide a radioligand suitable for clinical and pharmacological investigations of central 5-HT1A receptors in man using PET.

UI MeSH Term Description Entries
D008297 Male Males
D010879 Piperazines Compounds that are derived from PIPERAZINE.
D011725 Pyridines Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
D011869 Radioligand Assay Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders). Protein-Binding Radioassay,Radioreceptor Assay,Assay, Radioligand,Assay, Radioreceptor,Assays, Radioligand,Assays, Radioreceptor,Protein Binding Radioassay,Protein-Binding Radioassays,Radioassay, Protein-Binding,Radioassays, Protein-Binding,Radioligand Assays,Radioreceptor Assays
D011985 Receptors, Serotonin Cell-surface proteins that bind SEROTONIN and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. 5-HT Receptor,5-HT Receptors,5-Hydroxytryptamine Receptor,5-Hydroxytryptamine Receptors,Receptors, Tryptamine,Serotonin Receptor,Serotonin Receptors,Tryptamine Receptor,Tryptamine Receptors,Receptors, 5-HT,Receptors, 5-Hydroxytryptamine,5 HT Receptor,5 HT Receptors,5 Hydroxytryptamine Receptor,5 Hydroxytryptamine Receptors,Receptor, 5-HT,Receptor, 5-Hydroxytryptamine,Receptor, Serotonin,Receptor, Tryptamine,Receptors, 5 HT,Receptors, 5 Hydroxytryptamine
D001923 Brain Chemistry Changes in the amounts of various chemicals (neurotransmitters, receptors, enzymes, and other metabolites) specific to the area of the central nervous system contained within the head. These are monitored over time, during sensory stimulation, or under different disease states. Chemistry, Brain,Brain Chemistries,Chemistries, Brain
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D012702 Serotonin Antagonists Drugs that bind to but do not activate serotonin receptors, thereby blocking the actions of serotonin or SEROTONIN RECEPTOR AGONISTS. 5-HT Antagonist,5-HT Antagonists,5-Hydroxytryptamine Antagonist,5-Hydroxytryptamine Antagonists,Antiserotonergic Agent,Antiserotonergic Agents,Serotonin Antagonist,Serotonin Blockader,Serotonin Blockaders,Serotonin Receptor Antagonist,Serotonin Receptor Blocker,Antagonists, 5-HT,Antagonists, 5-Hydroxytryptamine,Antagonists, Serotonin,Serotonin Receptor Antagonists,Serotonin Receptor Blockers,5 HT Antagonist,5 HT Antagonists,5 Hydroxytryptamine Antagonist,5 Hydroxytryptamine Antagonists,Agent, Antiserotonergic,Agents, Antiserotonergic,Antagonist, 5-HT,Antagonist, 5-Hydroxytryptamine,Antagonist, Serotonin,Antagonist, Serotonin Receptor,Antagonists, 5 HT,Antagonists, 5 Hydroxytryptamine,Antagonists, Serotonin Receptor,Blockader, Serotonin,Blockaders, Serotonin,Blocker, Serotonin Receptor,Blockers, Serotonin Receptor,Receptor Antagonist, Serotonin,Receptor Antagonists, Serotonin,Receptor Blocker, Serotonin,Receptor Blockers, Serotonin
D014055 Tomography, Emission-Computed Tomography using radioactive emissions from injected RADIONUCLIDES and computer ALGORITHMS to reconstruct an image. CAT Scan, Radionuclide,CT Scan, Radionuclide,Computerized Emission Tomography,Radionuclide Tomography, Computed,Scintigraphy, Computed Tomographic,Tomography, Radionuclide-Computed,Computed Tomographic Scintigraphy,Emission-Computed Tomography,Radionuclide Computer-Assisted Tomography,Radionuclide Computerized Tomography,Radionuclide-Computed Tomography,Radionuclide-Emission Computed Tomography,Tomography, Computerized Emission,CAT Scans, Radionuclide,CT Scans, Radionuclide,Computed Radionuclide Tomography,Computed Tomography, Radionuclide-Emission,Computer-Assisted Tomographies, Radionuclide,Computer-Assisted Tomography, Radionuclide,Computerized Tomography, Radionuclide,Emission Computed Tomography,Emission Tomography, Computerized,Radionuclide CAT Scan,Radionuclide CAT Scans,Radionuclide CT Scan,Radionuclide CT Scans,Radionuclide Computed Tomography,Radionuclide Computer Assisted Tomography,Radionuclide Computer-Assisted Tomographies,Radionuclide Emission Computed Tomography,Scan, Radionuclide CAT,Scan, Radionuclide CT,Scans, Radionuclide CAT,Scans, Radionuclide CT,Tomographic Scintigraphy, Computed,Tomographies, Radionuclide Computer-Assisted,Tomography, Computed Radionuclide,Tomography, Emission Computed,Tomography, Radionuclide Computed,Tomography, Radionuclide Computer-Assisted,Tomography, Radionuclide Computerized,Tomography, Radionuclide-Emission Computed
D017207 Rats, Sprague-Dawley A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company. Holtzman Rat,Rats, Holtzman,Sprague-Dawley Rat,Rats, Sprague Dawley,Holtzman Rats,Rat, Holtzman,Rat, Sprague-Dawley,Sprague Dawley Rat,Sprague Dawley Rats,Sprague-Dawley Rats

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