3-(2'-[18F]Fluoroethyl)Spiperone: In vivo Biochemical and Kinetic Characterization in Rodents, Nonhuman Primates, and Humans
| Autor: | Nagichettiar Satyamurthy, Michael E. Phelps, Robert F. Ackermann, Randy E. Keen, John C. Mazziotta, Sung-Cheng Huang, Mark M. Bahn, Charna H. K. Nissenson, Jorge R. Barrio, John M. Hoffman |
|---|---|
| Rok vydání: | 1989 |
| Předmět: |
Male
Fluorine Radioisotopes Spiperone medicine.medical_specialty Striatum Tritium Receptors Dopamine Mice Species Specificity Dopamine Internal medicine Radioligand medicine Animals Humans Tissue Distribution 5-HT receptor Receptors Dopamine D2 Chemistry Brain Rats Inbred Strains Corpus Striatum Rats Kinetics Endocrinology Neurology Dopamine receptor Cardiovascular agent Autoradiography Neurology (clinical) Macaca nemestrina Cardiology and Cardiovascular Medicine Butaclamol Tomography Emission-Computed medicine.drug |
| Zdroj: | Journal of Cerebral Blood Flow & Metabolism. 9:830-839 |
| ISSN: | 1559-7016 0271-678X |
| DOI: | 10.1038/jcbfm.1989.117 |
| Popis: | 3-(2'-[18F]fluoroethyl)spiperone (FESP), a recently developed dopamine D2-receptor binding radiopharmaceutical, was used for dynamic characterization of dopamine-receptor binding in Macaca nemestrina monkeys and humans with positron emission tomography (PET). FESP in vitro binding properties to the dopamine receptor (IC50= 1.5 n M) are similar to those of spiperone. Serial PET scans in monkeys after intravenous bolus injection of FESP revealed specific radioactivity accumulation in striatum (rich in dopamine D2-receptors), whereas radioactivity concentration declined after 20 min in frontal cortex (serotonin receptors) and more rapidly in cerebellum (nonspecific binding). Specific dopamine D2-receptor binding was saturated with increasing concentrations of radioligand (specific activity range: 1–10,000 Ci/mmol), was stereospecifically blocked with (+)butaclamol (0.5 mg/kg), and showed only partial displacement with spiperone (200 μg/kg, i.v. administration 90 min after FESP injection). From PET experiments with FESP in humans, it is possible to visualize accumulation of radioactivity in striatum in a manner similar to that observed in monkeys and, ex vivo, in rodents (adult male Sprague-Dawley rats). Biochemical analyses in rat brain revealed that the activity (∼90%) in striatum was unmodified FESP up to 4 h after injection. On the other hand, FESP was metabolized peripherally (rat > monkey > human), with only 11% of plasma radioactivity remaining as intact FESP in rodents and 54% in humans after 2 h. Based on these interspecies scaling pharmacokinetic data, it is unequivocal that FESP peripheral metabolites do not significantly contribute to the accumulated radioactivity in striatal tissue. Therefore, it is concluded that FESP is suitable for the quantitative estimation of dopamine D2-receptor sites using PET. |
| Databáze: | OpenAIRE |
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