Positron emission tomography displacement sensitivity: Predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics

Evan D. Morris, Karmen Yoder

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its 'vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (ΔBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D2/D3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for ΔBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D2/D 3 tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.

Original languageEnglish
Pages (from-to)606-617
Number of pages12
JournalJournal of Cerebral Blood Flow and Metabolism
Volume27
Issue number3
DOIs
StatePublished - Mar 14 2007

Fingerprint

Positron-Emission Tomography
Dopamine
Raclopride
Amphetamine
Neurotransmitter Agents
Binding Sites
fallypride
3-N-(2-fluoroethyl)spiperone
epidepride

Keywords

  • Affinity constant
  • Amphetamine
  • Compartmental model
  • Competitive binding
  • Dopamine receptor
  • Neurotransmitter

ASJC Scopus subject areas

  • Endocrinology
  • Neuroscience(all)
  • Endocrinology, Diabetes and Metabolism

Cite this

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title = "Positron emission tomography displacement sensitivity: Predicting binding potential change for positron emission tomography tracers based on their kinetic characteristics",
abstract = "There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its 'vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (ΔBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D2/D3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for ΔBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D2/D 3 tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.",
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N2 - There is great interest in positron emission tomography (PET) as a noninvasive assay of fluctuations in synaptic neurotransmitter levels, but questions remain regarding the optimal choice of tracer for such a task. A mathematical method is proposed for predicting the utility of any PET tracer as a detector of changes in the concentration of an endogenous competitor via displacement of the tracer (a.k.a., its 'vulnerability' to competition). The method is based on earlier theoretical work by Endres and Carson and by the authors. A tracer-specific predictor, the PET Displacement Sensitivity (PDS), is calculated from compartmental model simulations of the uptake and retention of dopaminergic radiotracers in the presence of transient elevations of dopamine (DA). The PDS predicts the change in binding potential (ΔBP) for a given change in receptor occupancy because of binding by the endogenous competitor. Simulations were performed using estimates of tracer kinetic parameters derived from the literature. For D2/D3 tracers, the calculated PDS indices suggest a rank order for sensitivity to displacement by DA as follows: raclopride (highest sensitivity), followed by fallypride, FESP, FLB, NMSP, and epidepride (lowest). Although the PDS takes into account the affinity constant for the tracer at the binding site, its predictive value cannot be matched by either a single equilibrium constant, or by any one rate constant of the model. Values for ΔBP have been derived from published studies that employed comparable displacement paradigms with amphetamine and a D2/D 3 tracer. The values are in good agreement with the PDS-predicted rank order of sensitivity to displacement.

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