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Quantification of [11C]Raclopride PET studies

[11C]Raclopride (RP)

Raclopride 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 in the striatum with PET (Laruelle 2000). [11C]Raclopride (RP) is sensitive to competition from endogenous dopamine, and can be used in imaging of the changes in synaptic dopamine concentration in reproducible manner (Koepp et al., 1998; Wang t al., 1999).

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

Compartment model

Lammertsma et al. (1996) compared one- and two-tissue compartment models (1CM and 2CM), and found that two tissue compartments were required to achieve decent fit, also in cerebellum, but BP 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 DV values of striatum and cerebellum, calculated from K1-k4 (2CM) or K1-k2 (1CM) estimates.

Graphical analysis

Multiple time graphic analysis (MTGA) for reversible tracers (Logan plot) with metabolite corrected plasma input has been shown to provide reproducible DV and DVR maps (Wang et al., 1999). However, graphical analysis is known to produce biased estimates of DV and BP (Slifstein and Laruelle, 2000), although the bias is 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 ja BP) can be solved not only using traditional nonlinear fitting but also using linearized methods (leading to negative bias in BP in case of noisy data), or with basis function method (Gunn et al., 1997), which enable the calculation of binding potential (BPND) maps.

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 (BP=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 determined 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).

Parametric images

Simplified reference tissue model (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.

Binding potential maps

To produce parametric BPND images, the basis function method goes well together with the SRTM; program imgbfbp can be used for this purpose; provide the program with SIF for appropriate data weighting.

Regional BP calculation

Follow the instructions to calculate BPND from regional TACs with cerebellum as reference tissue. Use simplified reference tissue method (program fit_srtm and 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

Contact Jouni Pesonen.

Bolus studies with plasma input

Preparing the plasma input for modeling

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 modeling.

You need to have the measured hematocrit value and four data files:

  1. Blood file from the online sampler (*.bld, *.alg, *.lis):,
  2. count-rate file (*.cr, *.r, *.hc, *.head),
  3. manual plasma sample file (*ap.kbq) and
  4. fraction file of parent tracer in plasma (*.rat).

First, you need to make the necessary corrections to the blood online sampler data. Conversion of resulting blood curve to plasma is done with b2plasma with measured hematocrit and with knowledge that neither RP or its labelled metabolites cross the red blood cell membrane (use norbc with b2plasma). Thereafter, combine the online sampler derived plasma curve with the plasma curve from manual sampling.

If the tissue vascular volume fraction is to be considered in the modeling, the blood curve should now be calculated from the combined plasma curve using p2blood.

Then, the RP plasma curve is corrected for radioactive metabolites. Fraction data can be fitted with Hill-type function with default settings.

Metabolite corrected plasma curve is then corrected for time delay. Blood curve that was made previously can be corrected simultaneouly. The count-rate file is required in this step.

Resulting metabolite and time delay corrected plasma curve can then be used as input for modeling RP binding.

Vascular volume fraction

Time delay corrected blood curve can be used to correct the PET image or regional data for the impact of blood activity in tissue vasculature.

Parametric images with plasma input

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

Estimate a DV 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 BP images with plasma input, first calculate the mean DV inside cerebellum ROI from the DV image. Then, divide the DV image with this cerebellum DV value, using ecatcalc, for example:

ecatcalc ra1234dv.v : 1.325 ra1234dvr.v

and then subtract 1.0 from it, for example:

ecatcalc ra1234dvr.v - 1 ra1234bp.v

Regional analysis with plasma input

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


References:

Farde L, Ehrin E, Eriksson L, Greitz T, Hall H, Hedström C-G, Litton J-E, Sedvall G. Substituted benzamides as ligands for visualization of dopamine receptor binding in the human brain by positron emission tomography. Proc Natl Acad Sci USA 1985; 82: 3863-3867.

Farde L, Eriksson L, Blomquist G, Halldin C. Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET - a comparison to the equilibrium analysis. J Cereb Blood Flow Metab. 1989; 9(5): 696-708.

Gunn RN, Lammertsma AA, Hume SP, Cunningham VJ. Parametric imaging of ligand-receptor binding in PET using a simplified reference region model. Neuroimage 1997; 6:279-287.

Ito H, Hietala J, Blomqvist G, Halldin C, Farde L. Comparison of the transient equilibrium and continuous infusion method for quantitative PET analysis of [11C]raclopride binding. J Cereb Blood Flow Metab. 1998; 18: 941-950.

Koepp MJ, Gunn RN, Lawrence AD, Cunningham VJ, Dagher A, Jones T, Brooks DJ, Bench CJ, Grasby PM. Evidence for striatal dopamine release during a video game. Nature 1998; 393: 266-268.

Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, Frackowiak RSJ. Comparison of methods for analysis of clinical [11C]Raclopride studies. J Cereb Blood Flow Metab. 1996; 16: 42-52.

Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4:153-158.

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

Slifstein M, Laruelle M. Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med. 2000; 41: 2083-2088.

Olsson H, Farde L. Potentials and pitfalls using high affinity radioligands in PET and SPET determinations on regional drug induced D2 receptor occupancy - a simulation study based on experimental data. Neuroimage 2001; 14(4): 936-945.

Wang G-J, Volkow ND, Fowler JS, Logan J, Pappas NR, Wong CT, Hitzemann RJ, Netusil N. Reproducibility of repeated measures of endogenous dopamine competition with [11C]raclopride in the human brain in response to methylphenidate. J Nucl Med. 1999; 40: 1285-1291.


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