Quantification of [11C]-R-PK11195 PET studies
PK11195 is a selective ligand for the translocator protein (TSPO), formerly known as peripheral benzodiazepine receptor (PBR).
Analysis methods used in literature
Schuitemaker et al. (2007a) published an extensive comparison of methods for producing parametric images of [11C]-R-PK11195 binding. They suggest that when plasma input is available the Logan graphical analysis should be used (30-60 min linear fit), and with reference region input RPM1 (original version by Gunn et al. 1997) should be used, provided that the range of basis functions is carefully optimized.
2-tissue compartment model with plasma input
Kropholler et al. (2004) have validated the use of 2-tissue compartment model in estimating the total distribution volume (VT) and binding potential (k3/k4). VB was fitted, but K1/k2 was fixed to whole cortex value. With another tracer for peripheral benzodiazepine receptor ([11C]DAA1106) K1/k2 was found to differ among individuals (Ikoma et al., 2007), suggesting that k3/k4 should be preferred over VT.
Reference tissue input
Because glial cells are located everywhere in the brain, there is no true reference region for [11C]-R-PK11195 binding. Therefore, cluster analysis has been applied in extracting a reference tissue curve from the dynamic image, and it is used as input function for the simplified reference tissue model (Banati et al., 2000; Kropholler et al., 2006 and 2007).
However, the unsupervised tissue classification does not succeed in finding a reference tissue curve in all cases, and therefore a supervised clustering algorithm has been developed and validated (Turkheimer et al. 2007), and Matlab software Super-PK is available for this purpose. Reference region curve was then used to estimate binding potential (BPND) with simplified reference tissue model (SRTM) and rank-shaping regularized exponential spectral analysis (RS-ESA). Wavelet-based Logan plot, basis pursuit and SRTM give better ICC than ratio or traditional Logan method (Anderson et al., 2007).
For certain diseases it has been shown that cerebellum or certain cortical regions do not have increased microglial burden, and then these regions can be used as reference region for reference tissue model (Gerhard et al., 2002; 2005). Cerebellar grey matter can be used as reference tissue for quantifying TSPO expression in human glioma (Su et al., 2015).
Ratio method with white matter as reference tissue
Hammoud et al. (2005) validated by simulations the calculation of tissue-to-white matter ratio as a parameter related to binding potential. They calculated the ratio from 10 to 60 min p.i.. Unfortunately this method was not included in the comparison by Schuitemaker et al. (2007).
Suggested analysis method for Turku
[11C]-R-PK11195 has radioactive metabolites in the plasma and at least [11C]CH2O (formaldehyde) easily penetrates the blood-brain barrier (De Vos et al., 1999). The uptake of labelled metabolites in the brain precludes perfect quantification of peripheral benzodiazepine receptors, but an index related to the receptor concentration can still be achieved.
When plasma curves corrected for radioactive metabolites (Roivainen et al., 2009) are available, the method of Kropholler et al. (2004) is preferable choice for analysis method for regional data. To calculate parametric VT images the Logan graphical analysis is recommended (Schuitemaker et al., 2007), although a strictly linear phase can not be achieved.
When plasma curves are not available, the very simple method by Hammoud et al. (2005) seems like worth testing. Ratio image can be calculated e.g. using program imgratio. However, if precise quantitation is needed and extraction of valid reference tissue curves is possible (supervised cluster analysis is available in TPC; contact Jouni Tuisku), then RPM1 method is recommended (Schuitemaker et al., 2012), using PMOD or imgbfbp. Set the range of basis functions to the values determined for use with [11C]-R-PK11195 in TPC (contact Jouni Tuisku).
11C-R-PK11195 PET imaging allows noninvasive in vivo imaging and quantification of macrophages in rheumatoid synovitis, and possibly even in subclinical synovitis (van der Laken et al., 2008; Kropholler et al., 2009). Noninvasive visualization of macrophages may be useful both for detecting early synovitis and for monitoring synovitis activity during treatment (van der Laken et al., 2008; Gent et al., 2012; Roivainen et al., 2013).
Analysis methods used in literature
van der Laken et al. (2008) reported that 1-tissue compartment model with arterial plasma input can be used to estimate regional volume of distribution (VT) of [11C]-R-PK11195 in synovial tissue, and that [11C]-R-PK11195 uptake in synovial tissue was due to binding to TSPO on macrophages.
van der Laken et al. (2008) also found a good correlation between VT and SUV40-60, as well as good correlation between SUV40-60 and macrophage infiltration in synovial tissue. Kropholler et al. (2009) recommended calculating SUV20-40 in clinical use. Therefore, the scanning procedure could be simplified and shortened to a 20-minute static scan of joints of interest. This would make it a method that could be applied in routine clinical practice (van der Laken et al., 2008; Kropholler et al., 2009), and in whole-body imaging.
A simple scoring based on visual analysis may be useful in following arthritis activity (Gent et al., 2012 and 2014).
Suggested analysis method for Turku PET Centre
When plasma curves corrected for radioactive
metabolites are available the 1-tissue compartment
model fitting of van der Laken et al. (2008) is preferable choice for analysis method for
To calculate parametric VT images the Logan
graphical analysis may be recommended
For clinical routine analysis, and when plasma curves are not available, the SUV images can be computed, preferably from 20 to 40 min after injection.
For research purposes the supervised clustering method can be applied to extract the reference tissue curve (Rissanen et al., 2014).
- Blood data file from online blood sampler
*.bld, *.alg, *.lis, *.txt)),
Plasma TAC file from manual sampling
*.cr, *.r, *.hc, *.head or *.dft),
fraction file of parent tracer in plasma
- Haematocrit (e.g. 0.40)
In addition, user has to give the names of output files:
- Parent tracer TAC in plasma (e.g. *apc.kbq),
- Metabolite TAC in plasma (e.g. *apm.kbq),
- Blood TAC (*ab.kbq).
Output TACs are calibrated and corrected for physical decay, and delay-time). In addition, the script will create SVG and/or PNG images where the user can verify how fit of an exponential function into the fraction data succeeded, how delay correction succeeded, and how the resulting curves look like.
Dispersion correction is not applied in this script because the effect of dispersion is minimal in case of an 11C labelled tracer with relatively slow kinetics.
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Updated at: 2018-05-14
Created at: 2007-01-29
Written by: Vesa Oikonen