Abstract
A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t† after which a plot of ∫0 tROI(t′)dt′/ROI(t) versus ∫0 tCp(t′)dt′/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume, Vp. For a two-compartment model, the slope is given by λ + Vp, where λ is the partition coefficient and the intercept is - 1/[k2(1 + Vp/λ)]. For a three-compartment model, the slope is λ(1 + Bmax/Kp) + Vmax and the intercept is -{(1 + Bmax/Kd)/k2 + (koff(1 + Kd/Bmax)]-1} [1 + Vp/λ(1 + BmaxKd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 ± 0.20, in agreement with literature values.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 740-747 |
| Number of pages | 8 |
| Journal | Journal of Cerebral Blood Flow and Metabolism |
| Volume | 10 |
| Issue number | 5 |
| State | Published - 1990 |
| Externally published | Yes |
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Keywords
- Cocaine
- Compartmental modeling
- Graphical analysis
- PET
- Receptors
- Transfer constants
ASJC Scopus subject areas
- Endocrinology
- Neuroscience(all)
- Endocrinology, Diabetes and Metabolism
Cite this
Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. / Logan, Jean; Fowler, Joanna S.; Volkow, Nora D.; Wolf, Alfred P.; Dewey, Stephen L.; Schlyer, David J.; MacGregor, Robert R.; Hitzemann, Robert; Bendriem, Bernard; John Gatley, S.; Christman, David R.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 10, No. 5, 1990, p. 740-747.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects
AU - Logan, Jean
AU - Fowler, Joanna S.
AU - Volkow, Nora D.
AU - Wolf, Alfred P.
AU - Dewey, Stephen L.
AU - Schlyer, David J.
AU - MacGregor, Robert R.
AU - Hitzemann, Robert
AU - Bendriem, Bernard
AU - John Gatley, S.
AU - Christman, David R.
PY - 1990
Y1 - 1990
N2 - A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t† after which a plot of ∫0 tROI(t′)dt′/ROI(t) versus ∫0 tCp(t′)dt′/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume, Vp. For a two-compartment model, the slope is given by λ + Vp, where λ is the partition coefficient and the intercept is - 1/[k2(1 + Vp/λ)]. For a three-compartment model, the slope is λ(1 + Bmax/Kp) + Vmax and the intercept is -{(1 + Bmax/Kd)/k2 + (koff(1 + Kd/Bmax)]-1} [1 + Vp/λ(1 + BmaxKd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 ± 0.20, in agreement with literature values.
AB - A graphical method of analysis applicable to ligands that bind reversibly to receptors or enzymes requiring the simultaneous measurement of plasma and tissue radioactivities for multiple times after the injection of a radiolabeled tracer is presented. It is shown that there is a time t† after which a plot of ∫0 tROI(t′)dt′/ROI(t) versus ∫0 tCp(t′)dt′/ROI(t) (where ROI and Cp are functions of time describing the variation of tissue radioactivity and plasma radioactivity, respectively) is linear with a slope that corresponds to the steady-state space of the ligand plus the plasma volume, Vp. For a two-compartment model, the slope is given by λ + Vp, where λ is the partition coefficient and the intercept is - 1/[k2(1 + Vp/λ)]. For a three-compartment model, the slope is λ(1 + Bmax/Kp) + Vmax and the intercept is -{(1 + Bmax/Kd)/k2 + (koff(1 + Kd/Bmax)]-1} [1 + Vp/λ(1 + BmaxKd)]-1 (where Bmax represents the concentration of ligand binding sites and Kd the equilibrium dissociation constant of the ligand-binding site complex, koff (k4) the ligand-binding site dissociation constant, and k2 is the transfer constant from tissue to plasma). This graphical method provides the ratio Bmax/Kd from the slope for comparison with in vitro measures of the same parameter. It also provides an easy, rapid method for comparison of the reproducibility of repeated measures in a single subject, for longitudinal or drug intervention protocols, or for comparing experimental results between subjects. Although the linearity of this plot holds when ROI/Cp is constant, it can be shown that, for many systems, linearity is effectively reached some time before this. This analysis has been applied to data from [N-methyl-11C]-(-)-cocaine ([11C]cocaine) studies in normal human volunteers and the results are compared to the standard nonlinear least-squares analysis. The calculated value of Bmax/Kd for the high-affinity binding site for cocaine is 0.62 ± 0.20, in agreement with literature values.
KW - Cocaine
KW - Compartmental modeling
KW - Graphical analysis
KW - PET
KW - Receptors
KW - Transfer constants
UR - http://www.scopus.com/inward/record.url?scp=0025127930&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0025127930&partnerID=8YFLogxK
M3 - Article
C2 - 2384545
AN - SCOPUS:0025127930
VL - 10
SP - 740
EP - 747
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 5
ER -