title: In vivo saturation kinetics of two dopamine transporter probes measured using a small animal positron emission tomography scanner.
abstract: When estimated in vitro, the parameters which describe the binding of radiolabelled analogues of cocaine to sites on the dopamine transporter are very much influenced by the methodology used. In the present study, a small animal positron emission tomography (PET) scanner was used to estimate in vivo saturation kinetics for two carbon-11 labelled compounds presently used to monitor dopamine terminal function. The binding of [11C]CFT (WIN 35,428) in rat striatum was adequately described by a single-site model, giving an apparent dissociation constant corresponding to an intravenous dose of 242 nmol/kg. In contrast, the binding of [11C]RTI-121 was better described by a two-site model with the 'high-affinity' site or state (dissociation constant = 1 nmol/kg) being significantly occupied at doses routinely used in PET scanning. Such findings cannot readily be predicted from in vitro work, but could aid in both the choice of ligand and the model used in quantification of scan data. While multi-dose in vivo PET studies are difficult in man, rat PET can easily be employed either pre-clinically for putative radioligands, or experimentally, to study drug interactions and receptor occupancy related to functional efficacy.
authors.affiliation: PET Methodology Group, Hammersmith Hospital, London, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Hume
authors.forename: D J
authors.initials: DJ
authors.lastname: Brown
authors.forename: S
authors.initials: S
authors.lastname: Ashworth
authors.forename: E
authors.initials: E
authors.lastname: Hirani
authors.forename: S K
authors.initials: SK
authors.lastname: Luthra
authors.forename: A A
authors.initials: AA
authors.lastname: Lammertsma
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D017072:Neostriatum / Q000378:metabolism; D009419:Nerve Tissue Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000378:metabolism; D014055:Tomography, Emission-Computed / Q000379:methods*
chemical_list: D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D011954:Receptors, Dopamine; C079213:RTI 121; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine