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-HT1A 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 (DVCER) and
in regions of interest (DVROI), and calculating
BP = DVROI-DVCER. 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 = (DVROI-DVCER)/r1, where
r1 (plasma free fraction) was determined individually with
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 = (DVROI-DVCER)/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-HT1A
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 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
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.
imglhdv. BP maps can thereafter
be computed by subtraction, using e.g.
and cerebellar white matter as the reference region.
Note that the in vivo binding of [carbonyl-11C]WAY-100635
to postsynaptic 5-HT1A is not sensitive to endogenous 5-HT
(Maeda et al., 2001).
Andrée B, Halldin C, Pike VW, Gunn RN, Olsson H, Farde L. The PET
radioligand [carbonyl-11C]desmethyl-WAY-100635 binds to
5-HT1A receptors and provides a higher radioactive signal than
[carbonyl-11C]WAY-100635 in the human brain. J Nucl Med.
2002; 43(3): 292-303.
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):
Bhagwagar Z, Montgomery AJ, Grasby PM, Cowen PJ. Lack of effect of a
single dose of hydrocortisone on serotonin1A receptors in
revovered depressed patients measured by positron emission tomography with[11C]WAY-100635. Biol. Psychiatry 2003; 54: 890-895.
Bhagwagar Z, Rabiner EA, Sargent PA, Grasby PM, Cowen PJ. Persistent
reduction in brain serotonin1A receptor binding in recovered depressed men
measured by positron emission tomography with [11C]WAY-100635.
Mol Psychiatry. 2004; 9(4): 386-392.
Chou Y-H, Halldin C, Farde L. Occupancy of 5-HT1A receptors
by clozapine in the primate brain: a PET study. Psychopharmacology (Berl).
2003; 166(3): 234-240.
Cleare AJ, Messa C, Rabiner EA, Grasby PM. Brain 5-HT1A
receptor binding in chronic fatigue syndrome measured using positron emission
tomography and [11C]WAY-100635. Biol Psychiatry. 2005; 57(3):
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.
Farde L, Ito H, Swahn CG, Pike VW, Halldin C. Quantitative analyses
of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A
receptors in man. J. Nucl. Med. 1998; 39: 1965-1971.
Gunn RN, Lammertsma AA, Grasby PM. Quantitative analysis of
[carbonyl-11C]WAY-100635 PET studies. Nucl. Med. Biol.
Gunn RN, Sargent PA, Bench CJ, Rabiner EA, Osman S, Pike VW, Hume SP,
Grasby PM, Lammertsma AA. Tracer kinetic modeling of the 5-HT1A receptor
ligand (carbonyl-11C)WAY-100635 for PET. Neuroimage
1998; 8: 426-440.
Hirvonen J, Kajander J, Allonen T, Oikonen V, Någren K, Hietala J.
Measurement of serotonin 5-HT1A receptor binding using positron
emission tomography and [carbonyl-11C]WAY-100635 - Considerations on
the validity of cerebellum as a reference region. J Cereb Blood Flow Metab.
2007; 27(1): 185-195.
Ito H, Halldin C, Farde L. Localization of 5-HT1A
receptors in the living human brain using [Carbonyl-11C]WAY-100635:
PET with anatomic standardization technique. J. Nucl. Med. 1999;
Maeda J, Suhara T, Ogawa M, Okauchi T, Kawabe K, Zhang MR, Semba J,
Suzuki K. In vivo binding properties of [carbonyl-11C]WAY-100635:
effect of endogenous serotonin. Synapse 2001; 40(2): 122-129.
Oikonen V, Allonen T, Någren K, Kajander J, Hietala J. Quantification of
[Carbonyl-11C]WAY-100635 binding: considerations on the
cerebellum. Nucl. Med. Biol. 2000; 27:483-486.
Parsey RV, Arango V, Olvet DM, Oquendo MA, Van Heertum RL, John Mann J.
Regional heterogeneity of 5-HT1A receptors in human cerebellum
as assessed by positron emission tomography. J Cereb Blood Flow Metab.
Parsey RV, Oquendo MA, Ogden RT, Olvet DM, Simpson N, Huang YY, Van
Heertum RL, Arango V, Mann JJ. Altered Serotonin 1A Binding in Major
Depression: A [carbonyl-C-11]WAY100635 Positron Emission Tomography Study.
Biol Psychiatry. 2005b; (in press).
Parsey RV, Oquendo MA, Simpson NR, Ogden RT, Van Heertum R, Arango V,
Mann JJ. Effects of sex, age, and aggressive traits in man on brain
serotonin 5-HT1A receptor binding potential measured by PET using
[C-11]WAY-100635. Brain Res. 2002; 954(2): 173-182. <+pdf>
Parsey RV, Slifstein M, Hwang D-R, Abi-Dargham A, Simpson N, Mawlawi O,
Guo N-N, Van Heertum R, Mann JJ, Laruelle M. Validation and reproducibility
of measurement of 5-HT1A receptor parameters with[carbonyl-11C]WAY-100635 in humans: comparison of arterial
and reference tissue input functions. J. Cereb. Blood Flow Metab. 2000;
Passchier J, van Waarde A. Visualisation of serotonin-1A
(5-HT1A) receptors in the central nervous system. Eur. J. Nucl.
Med. 2001; 28:113-129.
Price JC, Kelley DE, Ryan CM, Meltzer CC, Drevets WC, Mathis CA, Mazumdar
S, Reynolds III CF. Evidence of increased serotonin-1A receptor binding in
type 2 diabetes: a psoitron emission tomography study. Brain Res. 2002;
Rabiner EA, Gunn RN, Wilkins MR, Sargent PA, Mocaer E, Sedman E, Cowen PJ,
Grasby PM. Drug action at the 5-HT1A receptor in vivo:
autoreceptor and postsynaptic receptor occupancy examined with PET and
[carbonyl-11C]WAY-100635. Nucl. Med. Biol. 2000;
Rabiner EA, Messa C, Sargent PA, Husted-Kjaer K, Montgomery A, Lawrence
AD, Bench CJ, Gunn RN, Cowen P, Grasby PM. A database of
[11C]WAY-100635 binding to 5-HT1A receptors in normal
male volunteers: normative data and relationship to methodological,
demographic, physiological, and behavioral variables. NeuroImage 2002;
Savic I, Lindstrom P, Gulyás B, Halldin C, Andrée B, Farde L. Limbic
reductions of 5-HT1A receptor binding in human temporal lobe
epilepsy. Neurology 2004; 62(8): 1343-1351.
Stein P, Savli M, Wadsak W, Mitterhauser M, Fink M, Spindelegger C,
Mien L-K, Moser U, Dudczak R, Kletter K, Kasper S, Lanzenberger R.
The serotonin-1A receptor distribution in healthy men and women measured by PET
and [carbonyl-11C]WAY-100635. Eur J Nucl Med Mol Imaging
2008; 35: 2159-2168.
Tauscher J, Kapur S, Verhoeff NP, Hussey DF, Daskalakis ZJ,
Tauscher-Wisniewski S, Wilson AA, Houle S, Kasper S, Zipursky RB. Brain
serotonin 5-HT1A receptor binding in schizophrenia measured by
positron emission tomography and [11C]WAY-100635. Arch Gen
Psychiatry 2002; 59(6): 514-520.
Tauscher J, Verhoeff PLG, Christensen BK, Hussey D, Meyer JH, Kecojevic A,
Javanmard M, Kasper S, Kapur S. Serotonin 5-HT1A receptor binding
potential declines with age as measured by [11C]WAY-100635 and
PET. Neuropsychopharmacology 2001; 24:522-530.
Turner MR, Rabiner EA, Hammers A, Al-Chalabi A, Grasby PM, Shaw CE, Brooks
DJ, Leigh PN. [11C]-WAY100635 PET demonstrates marked
5-HT1A receptor changes in sporadic ALS. Brain 2005; 128(Pt 4):
Wu S, Ogden RT, Mann JJ, Parsey RV. Optimal metabolite curve fitting for
kinetic modeling of 11C-WAY-100635. J Nucl Med. 2007; 48: