Research paper
In vivo saturation kinetics of two dopamine transporter probes measured using a small animal positron emission tomography scanner

https://doi.org/10.1016/S0165-0270(97)00078-2Get rights and content

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.

References (33)

  • DJ Brown et al.

    Synthesis of the dopamine re-uptake marker [124I]RTI-121

    J Labelled Compd Radiopharm

    (1997)
  • RF Dannals et al.

    Synthesis of a radiotracer for studying dopamine uptake sites in vivo using PET: 2β-carbomethoxy-3β-(4-fluorophenyl)-[N-11C-methyl]tropane ([11C]CFT or [11C]WIN-35,428

    J Labelled Compd Radiopharm

    (1993)
  • GD D'Mello et al.

    Conditioned taste aversion and operant behavior in rats: effects of cocaine, apomorphine and some long-acting derivatives

    J Pharmacol Exp Ther

    (1981)
  • L Farde et al.

    Examination of [C-11]β-CIT-FP and [C-11]β-CIT-FE uptake in the human brain by PET

    J Nucl Med

    (1996)
  • L Farde et al.

    PET study of [11C]β-CIT binding to monoamine transporters in the monkey and human brain

    Synapse

    (1994)
  • JJ Frost et al.

    Positron emission tomographic imaging of the dopamine transporter with 11C-WIN 35,428 reveals marked declines in mild Parkinson's disease

    Ann Neurol

    (1993)
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    Present address: PET Centre, Free University Hospital, PO Box 7057, 1007 MB Amsterdam, Netherlands.

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