Measuring receptor occupancy

Excellent reviews on PET methods used to measure receptor occupancy have been written by Laruelle (2000) and Passhier et al (2002).

Can we use high-affinity radioligands?


If there is a state of equilibrium between administrated or endogenous and tracer ligands, free receptor and receptor-ligand complexes, radioligand affinity should not affect measurement of occupancy by administrated or endogenous ligand. Yet, a frequent observation from several studiesis that the lower affinity radiotracers appear to be more susceptible to competition by synaptic endogenous or administered ligands than radiotracers which have very high receptor affinity.

... if equilibrium is achieved

It has been suggested that the magnitude of the competition is not reduced by the relative difference in ligand affinities, but by failure of the receptor binding of high-affinity radioligands to rapidly attain equilibrium [Gatley et al 2000, Laruelle et al 2000]. It is important that equilibrium is achieved within the time scale of the in vivo binding experiment with PET. Under conditions in which the radiotracer binding is still far from reaching equilibrium with the tissue receptors, radiotracer accumulation in the tissue is determined mostly by delivery (perfusion and transport) rather than by density of available receptors.

Even radiotracers which bind their receptors with an affinity so high that the binding is nearly irreversible in the time available for PET can be used to monitor receptor blockade, if proper modelling is applied [Ishizu et al 2000, Laruelle 2000].

Instead of different affinities, a possible explanation for differing competition results obtained with different tracers is matter of different ability to access the internalized receptors [Laruelle 2000].

Error sources

Partial volume effect

Measured occupancy is independent of partial volume effect [Martinez et al 2001].

Altered tracer delivery

Altered perfusion and peripheral clearance do no affect the receptor binding estimates calculated using graphical analysis or compartmental kinetic modelling [Laruelle 2000]. However, these methods are vulnerable to variations in blood flow or clearance that occur during the PET scan [Laruelle 2000]. Therefore, displacement experiments performed during the washout phase of the radiotracer are not appropriate to establishing an effect on receptor availability [Laruelle 2000].


Gatley SJ, Gifford AN, Carroll FI, Volkow ND. Sensitivity of binding of high-affinity dopamine receptor radioligands to increased synaptic dopamine. Synapse 2000; 38: 483-488.

Ishizu K, Smith DF, Bender D, Danielsen E, Hansen SB, Wong DF, Cumming P, Gjedde A. Positron emission tomography of radioligand binding in porcine striatum in vivo: haloperidol inhibition linked to endogenous ligand release. Synapse 2000; 38: 87-101.

Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 2000; 20: 423-451.

Martinez D, Hwang D-R, Mawlawi O, Slifstein M, Kent J, Simpson N, Parsey RV, Hashimoto T, Huang Y, Shinn A, Van Heertum R, Abi-Dargham A, Caltabiano S, Malizia A, Cowley H, Mann JJ, Laruelle M. Differential occupancy of somatodendritic and postsynaptic 5HT1A receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology 2001; 24:209-229. 

Olsson H, Halldin C, Farde L. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 2004; 22: 794-803.

Passchier J, Gee A, Willemsen A, Vaalburg W, van Waarde A. Measuring drug-related receptor occupancy with positron emission tomography. Methods 2002; 27: 278-286.

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