Radioligand studies: imaging and quantitative analysis

doi:10.1016/S0924-977X(02)00100-1

European Neuropsychopharmacology

Volume 12, Issue 6, December 2002, Pages 513-516

https://doi.org/10.1016/S0924-977X(02)00100-1 Get rights and content

Abstract

Radioligand studies enable visualisation and measurement of molecular pathways and pharmacokinetic processes. Using positron emission tomography, accurate measurements of the time course of radioligand uptake and clearance can be obtained. A tracer kinetic model is needed to derive physiological or pharmacokinetic parameters from these tissue time–activity curves. In addition, an input function that indicates delivery to the tissue is required. Usually this will be the arterial plasma curve. For receptor studies, where binding potential is the parameter of interest, it might also be possible to avoid arterial sampling provided a tissue can be defined that is devoid of receptors.

Section snippets

Principles

Positron emission tomography (PET) is a tomographic imaging technique, which allows for accurate non-invasive in vivo measurements of a wide range of regional tissue functions in man. Its use in imaging and measuring pre- and post-synaptic receptor density and affinity, neurotransmitter release, enzyme activity, and drug delivery and uptake is particularly interesting. This is due to its unrivalled sensitivity, which allows for quantification at the picomolar level. At present, PET represents

Imaging

Imaging of radioligand distribution at some stage after intravenous injection might actually provide an immediate overview of relative uptake in different regions of the brain. This is especially the case if the tracer is in secular equilibrium at the time of scanning, i.e. if the specific to non-specific ratio is constant. Even some form of quantification might be possible by comparing the uptake relative to a reference region without specific signal (receptors). It should be noted, however,

Tracer kinetics

At any given time, the in vivo brain signal is not only due to specific binding, but it also contains contributions from non-specific binding and free ligand in tissue. In addition, as the brain contains blood, intravascular activity will play a role. Following intravenous injection, free, non-specific, specific and intravascular concentrations are not constant, but vary with time. Moreover, the relative contribution of each of these components to the total signal, measured with PET (or SPECT),

Compartmental models

The various components mentioned above can be put together into a compartment model in which each component is a separate compartment. The rate of exchange between the various compartments is described by (unknown) rate constants. The result of such a compartment model is an operational equation that describes the radioligand concentration as measured by PET or SPECT (response) in terms of rate constants and the (measured) plasma input curve. This equation contains multiple unknown parameters

Input functions

It should be noted that the above operational equation contains two input functions. The metabolite-corrected arterial plasma curve determines the exchange with tissue. The intravascular activity, however, is at whole blood concentration and contains metabolites. Thus, both the metabolite-corrected arterial plasma and the non-corrected arterial whole blood curves are required. It is well-known that failure to correct for metabolites in the plasma curve might lead to ‘quantitative’ results that

Simplifications

Unfortunately, all parameters have to be obtained from a single time–activity curve. As a result, correlation between parameters is likely and the accuracy of individual fitted rate constants can be poor. To improve reproducibility, the model often is simplified. A common approach is to lump free and non-specific binding together into a single compartment, assuming that the exchange rate between them is so fast that they cannot be distinguished separately given the time resolution of the

Reference tissue models

Wherever possible, arterial cannulation should be avoided, especially for routine clinical applications. Recently, models have been described that relate the measured radioligand concentration in a receptor-rich region to that in a (reference) region, which is devoid of receptors. It is still possible to solve for binding parameters, provided the level of non-specific binding is the same in the target and reference region. In particular, the binding potential BP can be determined directly. In

Functional images

Usually, calculations are performed on a region of interest basis. It is clear that analyses should ideally be performed on a pixel-by-pixel basis, resulting in functional images, which could be analysed using statistical methods such as SPM (statistical parametric mapping). Unfortunately, nonlinear regression is sensitive to noise and, therefore, less suitable for analysing (noisy) pixel curves. Several linearised approaches (e.g. Patlak analysis, Logan analysis, weighted integration, spectral

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To quantify physiological processes measured with positron emission tomography (PET), the time course of the parent radioligand concentration in arterial plasma is usually required as an input function if a PET pharmacokinetic model is employed [1–3].
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European Neuropsychopharmacology

Abstract

Section snippets

Principles

Imaging

Tracer kinetics

Compartmental models

Input functions

Simplifications

Reference tissue models

Functional images

Further reading

References (13)

Parametric imaging of ligand–receptor binding in PET using a simplified reference region model

NeuroImage

Simplified reference tissue model for PET receptor studies

NeuroImage

Spectral analysis of dynamic PET data

J. Cereb. Blood Flow Metab.

Radioligand studies in brain: kinetic analysis of PET data

Med. Chem. Res.

Positron emission tomography compartmental models

J. Cereb. Blood Flow Metab.

Measurement of local blood flow and distribution volume with short-lived isotopes: a general input technique

J. Cereb. Blood Flow Metab.

Cited by (44)

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A Prediction Method for P-glycoprotein–Mediated Drug–Drug Interactions at the Human Blood–Brain Barrier From Blood Concentration–Time Profiles, Validated With PET Data

A simplified radiometabolite analysis procedure for PET radioligands using a solid phase extraction with micellar medium

" Mixed" anionic and non-ionic micellar liquid chromatography for high-speed radiometabolite analysis of positron emission tomography radioligands

Rapid metabolite analysis of positron emission tomography radioligands by direct plasma injection combining micellar cleanup with high submicellar liquid chromatography with radiometric detection

Rapid and sensitive measurement of PET radioligands in plasma by fast liquid chromatography/radiometric detection