Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands.
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Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands. / Wong, D F; Gjedde, A; Wagner, H N.
In: Journal of Cerebral Blood Flow and Metabolism, Vol. 6, No. 2, 1986, p. 137-46.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands.
AU - Wong, D F
AU - Gjedde, A
AU - Wagner, H N
PY - 1986
Y1 - 1986
N2 - A first step in the quantification of receptor density in the living human brain is the measurement of the binding of a labeled ligand to the receptor in question. In the present study, we determined the rate of binding of 11C-labeled N-methylspiperone (NMSP) to the D2 dopamine receptor in 11 normal volunteers, using a three-compartment model to relate the time integral of the measured plasma concentration to the distribution of the tracer in the caudate nucleus. The plasma concentrations of NMSP were separated from the contaminating metabolites by the ratio of radioactivities in cerebellum and blood plasma. Plasma concentrations calculated in this way agreed with plasma concentrations determined by HPLC. The rate of binding of labeled NMSP to its receptors (k3) was defined as the product of the bimolecular association rate (kon) and the quantity of available receptors (B'max) and calculated as the ratio between the steady-state rate of accumulation and the volume of distribution of labeled NMSP in the caudate nucleus. The average value of k3 in the 11 normal volunteers was 0.065 min-1. The fractional clearance of labeled NMSP from the caudate nucleus (k2) was 0.070 min-1 and thus close to the value of k3. We also examined several indexes of binding based on ratios between different regions in brain. The indexes required that binding be negligible compared to the efflux of labeled NMSP (i.e., k2 much greater than k3) and therefore yielded incorrectly low values of k3. Thus, the only accurate approach used measured plasma concentrations to estimate transfer constants at steady state and yielded the absolute rate of binding k3. The approach is applicable to other irreversibly bound ligands.
AB - A first step in the quantification of receptor density in the living human brain is the measurement of the binding of a labeled ligand to the receptor in question. In the present study, we determined the rate of binding of 11C-labeled N-methylspiperone (NMSP) to the D2 dopamine receptor in 11 normal volunteers, using a three-compartment model to relate the time integral of the measured plasma concentration to the distribution of the tracer in the caudate nucleus. The plasma concentrations of NMSP were separated from the contaminating metabolites by the ratio of radioactivities in cerebellum and blood plasma. Plasma concentrations calculated in this way agreed with plasma concentrations determined by HPLC. The rate of binding of labeled NMSP to its receptors (k3) was defined as the product of the bimolecular association rate (kon) and the quantity of available receptors (B'max) and calculated as the ratio between the steady-state rate of accumulation and the volume of distribution of labeled NMSP in the caudate nucleus. The average value of k3 in the 11 normal volunteers was 0.065 min-1. The fractional clearance of labeled NMSP from the caudate nucleus (k2) was 0.070 min-1 and thus close to the value of k3. We also examined several indexes of binding based on ratios between different regions in brain. The indexes required that binding be negligible compared to the efflux of labeled NMSP (i.e., k2 much greater than k3) and therefore yielded incorrectly low values of k3. Thus, the only accurate approach used measured plasma concentrations to estimate transfer constants at steady state and yielded the absolute rate of binding k3. The approach is applicable to other irreversibly bound ligands.
M3 - Journal article
C2 - 2937794
VL - 6
SP - 137
EP - 146
JO - Journal of Cerebral Blood Flow and Metabolism
JF - Journal of Cerebral Blood Flow and Metabolism
SN - 0271-678X
IS - 2
ER -
ID: 14944276