title: In vivo measures of dopaminergic radioligands in the rat brain: equilibrium infusion studies.
abstract: The application of an equilibrium infusion method for measuring specific in vivo radioligand binding in the conscious rat brain was evaluated for two ligands of the dopaminergic system, (+)-alpha-[(11)C]dihydrotetrabenazine (DTBZ) and d-threo-[(11)C]methylphenidate (MePhen). Both radioligands can be successfully utilized to reach equilibrium distributions in rat brain within 1 h; combinations of tritiated and carbon-11-labeled radiotracers can furthermore be used to obtain simultaneous measures of the neuronal membrane dopamine transporter (using [(3)H]MePhen) and vesicular monoamine transporter (using [(11)C]DTBZ) in the same animal. These studies provided quantitative measures of distribution volume ratios, which represent specific radioligand binding. Stereospecificity of in vivo binding was demonstrated using equilibrium infusions of the low-affinity isomers of each ligand, (-)-alpha-[(11)C]dihydrotetrabenazine (DTBZ) and l-threo-[(11)C]methylphenidate, both of which produced uniform brain distributions and no specific binding. Specific binding of (+)-alpha-[(11)C]dihydrotetrabenazine was blocked by co-infusion of tetrabenazine, but was unaffected by administration of methylphenidate, haloperidol, or apomorphine. Specific binding of d-threo-[(11)C]methylphenidate, conversely, was blocked with unlabeled methylphenidate but not affected by tetrabenazine or the dopamine receptor ligands. Equilibrium measures of in vivo radioligand binding, as utilized in this study, offer a quantitative means to evaluate acute and chronic drug effects on in vivo radioligand binding in the rat brain.
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, 3480 Kresge III Bldg., University of Michigan Medical School, Ann Arbor, MI 48109, USA. mkilbour@umich.edu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Kilbourn
authors.forename: Phillip S
authors.initials: PS
authors.lastname: Sherman
authors.forename: Kyle
authors.initials: K
authors.lastname: Kuszpit
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002250:Carbon Radioisotopes; D004298:Dopamine / Q000031:analogs & derivatives / Q000378:metabolism*; D015259:Dopamine Agents / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000378:metabolism; D007260:Infusion Pumps; D008024:Ligands; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism; D008774:Methylphenidate / Q000378:metabolism; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D009479:Neuropeptides; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013747:Tetrabenazine / Q000031:analogs & derivatives* / Q000378:metabolism; D014316:Tritium; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D014316:Tritium; D008774:Methylphenidate; C032811:dihydrotetrabenazine; D004298:Dopamine; D013747:Tetrabenazine