Quantification of [carbonyl-¹¹C]WAY-100635 PET studies

Analysis methods used in literature

Simplified reference tissue model (SRTM) with cerebellum as the reference region is widely used to analyze [¹¹C]WAY-100635 studies, both regionally and to form parametric binding maps (Rabiner et al. 2000; Tauscher et al. 2001, 2002; Price et al. 2002; Rabiner et al. 2002; Bhagwagar et al. 2003, 2004; Doder et al. 2003; Turner et al., 2005; Cleare et al., 2005; Stein et al., 2008). Price et al. (2002) got highly correlated binding estimates using SRTM and Logan analysis with cerebellum input. Binding parameters did not correlate with cerebral blood flow as measured with [¹⁵O]H₂O (Price et al. 2002).

Ito et al. (1999) computed "BP" maps by calculating first the TAC integrals from 12 to 63 min, and then dividing the integral value from each pixel by the integral in cerebellum, and finally subtracting 1 from the ratio. Resulting values were "in good agreement" with estimates calculated from the total distribution volumes. Time range 33-63 min was used in a primate study to determine the occupancy of 5-HT_1A receptors by clozapine (Chou et al., 2003). Regional peak equilibrium method and SRTM provide similar BP estimates, which are clearly lower than BP estimated using compartmental model with plasma input (Andrée et al., 2002).

Parsey et al. (2000) compared most applicable analysis methods in a test-retest study for regional data of five healthy subjects, and they suggest using unconstrained two-tissue compartment model fit with arterial metabolite corrected plasma as input to estimate distribution volumes (DV = (K1/k2)*(1+k3/k4)) in cerebellum (DV_CER) and in regions of interest (DV_ROI), and calculating BP = DV_ROI-DV_CER. This method provides the smallest bias (Parsey et al. 2005a). However, all tested methods provide binding parameters that are highly correlated (Parsey et al. 2000). Parsey et al. (2005a, 2005b) have also suggested using cerebellar white matter as reference region, and fitting one-tissue compartment model to this region; binding potential was then calculated as BP = (DV_ROI-DV_CER)/r₁, where r₁ (plasma free fraction) was determined individually with ultrafiltration technique.

Similarly, Logan's multiple-time graphical analysis (Logan plot) with plasma input was used to estimate DV for cerebellum and other regions (starting linear fit from 25 min) to estimate BP from the same equation BP = (DV_ROI-DV_CER)/r₁ (Bailer et al., 2005). Logan plot with cerebellum input (linear fit was started from 30 min) was used by Savic et al. (2004) to estimate regional BP as DVR-1.

Cerebellum as reference region

One-tissue compartment model can not satisfactorily fit the time-activity curves from cerebellum (Farde et al., 1998; Gunn et al., 1998; Parsey et al., 2000). This is due to the heterogeneity of cerebellum (Oikonen et al. 2000) and the relatively high concentration of 5-HT_1A receptors in the cerebellar vermis (Parsey et al. 2005a), and possibly uptake of a radioactive metabolite (Farde et al., 1998; Gunn et al., 1998).

To avoid artefactual changes in BP due to reference region variation, cerebellar ROI curves that are normalized to injected dose and subject weight or to the curves maxima (Cleare et al., 2005; Turner et al., 2005) should be plotted and subjects which have a clearly different cerebellar curve must then be excluded from the analysis.

Parsey et al. (2005a) suggested drawing the reference region on cerebellum white matter; these curves can be fitted by one-tissue compartment model. Test-retest analysis supported the use of cerebellar white matter as reference region to reduce bias when estimating BP from plasma-input derived distribution volumes, but not as direct reference input with reference input models (Hirvonen et al., 2007)

Plasma input

Plasma TAC must be corrected for metabolites, however metabolites cannot be determined reliably at late times. Therefore the fraction of parent tracer in plasma must be extrapolated, and the Hill function is recommended for this purpose (Wu et al., 2007).

Suggested analysis method for Turku

For most purposes, dynamic 90-min scans with no blood sampling can be considered to provide reliable (although somewhat biased) maps of [¹¹C]WAY-100635 binding. SRTM with cerebellum as reference region can be used as the analysis method. Parametric maps can be computed using imgbfbp or imgsrtm.

If very small population differences are being studied (for example, effect of age or gender), it may be necessary to collect arterial blood samples, analyze plasma metabolites and binding to plasma proteins. These are needed to compute distribution volume maps using e.g. imgdv or imglhdv. BP maps can thereafter be computed by subtraction, using e.g. ecatcalc, and cerebellar white matter as the reference region.

Note that the in vivo binding of [carbonyl-¹¹C]WAY-100635 to postsynaptic 5-HT_1A is not sensitive to endogenous 5-HT (Maeda et al., 2001).

References:

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Bailer UF, Frank GK, Henry SE, Price JC, Meltzer CC, Weissfeld L, Mathis CA, Drevets WC, Wagner A, Hoge J, Ziolko SK, McConaha CW, Kaye WH. Altered brain serotonin 5-HT1A receptor binding after recovery from anorexia nervosa measured by positron emission tomography and [carbonyl¹¹C]WAY-100635. Arch Gen Psychiatry 2005; 62(9): 1032-1041.

Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ. Lack of effect of a single dose of hydrocortisone on serotonin_1A receptors in revovered depressed patients measured by positron emission tomography with[¹¹C]WAY-100635. Biol. Psychiatry 2003; 54: 890-895.

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Doder M, Rabiner EA, Turjanski N, Lees AJ, Brooks DJ. Tremor in Parkinson's disease and serotonergic dysfunction: an ¹¹C-WAY 100635 PET study. Neurology 2003; 60(4): 601-605.

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