Quantification of [11C]Raclopride PET studies

Raclopride (RP) is a dopamine D2 receptor antagonist which, when labeled with 11C (Farde et al., 1985), is suitable and widely used for quantitative imaging of dopamine D2 receptors (D2R) in the striatum with PET (Laruelle 2000). [11C]Raclopride (RP) uptake is sensitive to competition from endogenous dopamine (DA), and can be used in imaging of the changes in synaptic dopamine concentration in reproducible manner (Koepp et al., 1998; Wang et al., 1999). When the DA concentration has returned to baseline levels, the agonist-induced D2-receptor internalization can be measured (Weinstein et al., 2017).

Caffeine increases striatal dopamine D2 receptor availability (Volkow et al., 2015), which should be taken into consideration in countries like Finland and Sweden where coffee consumption is very high.

Analysis methods for RP used in literature

[11C]Raclopride has a long time been one of the most widely used PET tracers, and even worked as a model tracer in development and validation of new analysis methods. Therefore, this is is not a comprehensive list of analysis methods for [11C]raclopride, but merely a list of models of practical use in Turku PET Centre.

Models with plasma input

Compartmental model

Lammertsma et al. (1996) compared one- and two-tissue compartment models (1TCM and 2TCM) with arterial plasma input function, and found that two tissue compartments were required to achieve decent fit, also in cerebellum, but BPND estimates from two-tissue compartment model had too high standard errors. The compartment model fit to the whole brain curve precede the regional fits to determine a common plasma delay time. Compartment model includes the blood volume. Binding potential was calculated from VT values of striatum and cerebellum.

Graphical analysis

Multiple time graphic analysis (MTGA) for reversible tracers (Logan plot) with metabolite corrected plasma input has been shown to provide reproducible VT and distribution volume ratio (DVR) maps (Wang et al., 1999). However, graphical analysis is known to produce biased estimates of VT and BPND (Slifstein and Laruelle, 2000), although the bias may be effectively canceled out of receptor occupancy estimates.

Models with reference tissue input

The cerebellum is nearly devoid of D2 and D3 receptors, and specific binding of RP is thought to be negligible in the cerebellum. Therefore, cerebellum is commonly used as reference tissue in RP PET studies.

Reference tissue compartment model

Simplified reference tissue model (SRTM) has since its introduction (Lammertsma and Hume, 1996) been the most popular method of analysis of RP PET data. The parameters of simplified model (R1, k2 and BPND) can be solved not only using traditional nonlinear fitting but also using linearized methods (leading to negative bias in BPND in case of noisy data), or with basis function method (Gunn et al., 1997), which enable the calculation of BPND maps. Choice of weights is important with the SRTM (Thiele & Buchert, 2008; Normandin et al., 2012). Long-term test-retest reliability studies have shown good reproducibility, even in thalamus (Alakurtti et al., 2015).

Endogenous dopamine release reduces RP binding, and the effect can be quantitated using SRTM extended with time-dependent activation function (Alpert et al., 2003; Bäckman et al., 2017).

Graphic analysis

Multiple time graphic analysis (MTGA) for reversible tracers (Logan plot) can be applied to RP PET data with cerebellum curve instead of metabolite corrected plasma input to produce DVR estimates (BPND=DVR-1). However, graphical analysis is known to produce biased estimates with noisy data (Slifstein and Laruelle, 2000).

Pseudo-equilibrium

In the classical method described by Farde et al. (1989), k3/k4 is estimated as Bound/Free (B/F) ratio at “transient equilibrium state”, at the peak time of striatum - cerebellum curve. Because the assumption of similar free tracer concentration in striatum and reference tissue (cerebellum) is not true, this method leads to biased binding estimates (Ito et al., 1998), although the effect on occupancy estimates is minimal (Olssson and Farde, 2001).

Since the peak time of bound curve is difficult to determine, a certain time range is often used. Nyberg et al. (1996) studied the test-retest reliability of putamen-to-cerebellum ratio at 9-45 min, and this method has since been used for example by Nordström et al. (1998).

Parametric images

SRTM solved with basis function method (BFM) is a fast and bias-free method to produce BPND images (Gunn et al., 1997).

Suggested analysis method for Turku

Bolus studies without arterial sampling

In clinical use, the simplified reference tissue model (SRTM) with cerebellum as the reference region is recommended.

To produce parametric BPND images, the basis function method goes well together with the SRTM; PMOD, or CLI program imgbfbp can be used for this purpose.

BPND can also be calculated from regional TACs using SRTM as instructed. Remember to weight the regional data before calculation.

Bolus+Infusion studies

RP PET studies that are conducted using bolus+infusion (BI) protocol can be analyzed simply by calculating tissue-to-reference tissue ratio after equilibrium has been reached. The time range where tissue curves are on a constant level must be determined visually by plotting the regional time-activity concentration curves. Thereafter, ratio during that time range can be calculated either regionally or to produce a ratio image.

ntPET

To analyze bolus+infusion studies using ntPET or other kinetic methods, please contact Jarkko Johansson or Jouni Tuisku.

Bolus studies with plasma input

Preparing the plasma input for modelling

A dedicated program for RP for corrections of plasma and blood data is not available, because [11C]raclopride studies do not usually include blood sampling. However, the low-level software can be used to prepare the input data for modelling.

If online blood sampling system is used, the blood TAC must be converted to plasma TAC. For RP we can assume that tracer does not pass the RBC membranes (select norbc with program b2plasma).

In RP studies the plasma parent fractions can be fitted using Hill-type function.

Vascular volume fraction

Time delay corrected blood curve can be used to correct the PET image or regional TAC data for the impact of blood activity in tissue vasculature, using either predetermined VB or by fitting VB as an additional compartmental model parameter.

Parametric images with plasma input

At present, strong filtering before modelling may be appropriate to reduce noise and noise-induced bias.

Estimate a VT image using dynamic PET image, previously corrected plasma TAC, and imglhdv with option -2, for example:

imglhdv -2 ra1234apc_delay.kbq ra1234dy1.v ra1234dv.v

To retrieve BPND images with plasma input, first calculate the mean VT inside cerebellum ROI from the VT image. Then, divide the VT image with this cerebellum VT value, using imgcalc, for example:

imgcalc ra1234dv.v : 1.325 ra1234dvr.v

and then subtract 1.0 from it, for example:

imgcalc ra1234dvr.v - 1 ra1234bp.v

Regional analysis with plasma input

Estimate regional VT, or DVR using cerebellum as reference region, using lhsoldv with option -2.



References:

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Created at: 2007-05-23
Updated at: 2017-08-22
Written by: Vesa Oikonen