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Quantification of [11C]-R-PK11195 brain PET studies

PK11195 is a selective ligand for the translocator protein (TSPO), formerly known as peripheral benzodiazepine receptor. Only low levels of TSPO is present in normal central nervous system, but in inflammation, higher densities of TSPO are found in activated microglia and macrophages.

For a thorough introduction, please read the review article written by Banati (2002).

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 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 DV.

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 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). Reference region curve was then used to estimate binding potential (BP) with simplified reference tissue model (SRTM) and rank-shaping regularized exponential spectral analysis (RS-ESA).

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).

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 from the injection. 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 labeled 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 are available the method of Kropholler et al. (2004) is preferrable choice for analysis method for regional data. To calculate parametric volume of distribution (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, then RPM1 method using imgbfbp is recommended. Currently, the range of basis functions is not yet determined for use with [11C]-R-PK11195 in TPC.

Processing of plasma data in TPC

A script called PK11195_input.vbs is available for corrections of plasma and blood data. As input it needs five files:

  1. Blood file from the online sampler (*.bld, *.alg, *.lis):,
  2. PET image file (*.img or *.v),
  3. count-rate file (*.cr, *.r, *.head or *.dft),
  4. manual plasma sample file (*p.kbq) and
  5. fraction file of parent tracer in plasma (*.rat).

and as output, the user will receive metabolite corrected plasma file, blood file and file with metabolite TAC. In addition, the script will create PostScript images where the user can verify how fit of a Hill function into the fraction data succeeded, how delay correction succeeded and how the result curves look like.

How to use the script

You can find a HTA user interface (PK11195_input.hta) on S:\pet-software\bin\windows and either copy and save it into your own computer or double click to open it from that directory. The names of input and output files should be filled to the form and then the execution button can be pressed. You will receive a message telling when the execution has ended. Do go through the created images to verify the success of the process!


References:

Banati RB, Newcombe J, Gunn RN, Cagnin A, Turkheimer F, Heppner F, Price G, Wegner F, Giovannoni G, Miller DH, Perkin GD, Smith T, Hewson AK, Bydder G, Kreutzberg GW, Jones T, Cuzner ML, Myers R. The peripheral benzodiazepine binding site in the brain in multiple sclerosis. Quantitative in vivo imaging of microglia as a measure of disease activity. Brain 2000; 123:2321-2337.

Banati RB. Visualising microglial activation in vivo. Glia 2002; 40(2): 206-217.

De Vos F, Dumont F, Santens P, Slegers G, Dierckx R, De Reuck J. High-performance liquid chromatographic determination of [11C]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide in mouse plasma and tissue and in human plasma. J. Chromatogr. B 1999; 736: 61-66.

Gerhard A, Schwarz J, Myers R, Wise R, Banati RB. Evolution of microglial activation in patients after ischemic stroke: a [11C](R)-PK11195 PET study. Neuroimage 2005; 24: 591-595.

Gerhard A, Watts J, Trender-Gerhard I, Turkheimer F, Banati RB, Bhatia K, Brooks DJ. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in corticobasal degeneration. Mov Disord. 2004; 19(10): 1221-1226.

Hammoud DA, Endres CJ, Chander AR, Guilarte TR, Wong DF, Sacktor NC, McArthur JC, Pomper MG. Imaging glial cell activation with [11C]-R-PK11195 in patients with AIDS. J. Neurovirol. 2005; 11(4): 346-355.

Ikoma Y, Yasuno F, Ito H, Suhara T, Ota M, Toyama H, Fujimura Y, Takano A, Maeda J, Zhang M-R, Nakao R, Suzuki K. Quantitative analysis for estimating binding potential of the peripheral benzodiazepine receptor with [11C]DAA1106. J. Cereb. Blood Flow Metab. 2007; 27: 173-184.

Kropholler MA, Boellaard R, Schuitemaker A, van Berckel BNM, Luurtsema G, Windhorst AD, Lammertsma AA. Development of a tracer kinetic plasma input model for (R)-[11C]PK11195 brain studies. J. Cereb. Blood Flow Metab. 2005; 25(7): 842-851.

Kropholler MA, Boellaard R, Schuitemaker A, Folkersma H, van Berckel BNM, Lammertsma AA. Evaluation of reference tissue models for the analysis of [11C](R)-PK11195 studies. J. Cereb. Blood Flow Metab. 2006; 26(11): 1431-1441.

Kropholler MA, Boellaard R, van Berckel BN, Schuitemaker A, Kloet RW, Lubberink MJ, Jonker C, Scheltens P, Lammertsma AA. Evaluation of reference regions for (R)-[11C]PK11195 studies in Alzheimer's disease and mild cognitive impairment. J. Cereb. Blood Flow Metab. 2007; 27(12): 1965-1974.

Schuitemaker A, van Berckel BNM, Kropholler MA, Kloet RW, Jonker C, Scheltens P, Lammertsma AA, Boellaard R. Evaluation of methods for generating parametric (R)-[11C]PK11195 binding images. J Cereb Blood Flow Metab. 2007a; 1603-1615.

Schuitemaker A, van Berckel BN, Kropholler MA, Veltman DJ, Scheltens P, Jonker C, Lammertsma AA, Boellaard R. SPM analysis of parametric (R)-[11C]PK11195 binding images: plasma input versus reference tissue parametric methods. Neuroimage 2007b; 35(4): 1473-1479.

Tomasi G, Edison P, Bertoldo A, Roncaroli F, Singh P, Gerhard A, Cobelli C, Brooks DJ, Turkheimer FE. Novel reference region model reveals increased microglial and reduced vascular binding of 11C-(R)-PK11195 in patients with Alzheimer's Disease. J Nucl Med. 2008; 49: 1249-1256.

Turkheimer FE, Edison P, Pavese N, Roncaroli F, Anderson AN, Hammers A, Gerhard A, Hinz R, Tai YF, Brooks DJ. Reference and target region modeling of [11C](R)-PK11195 brain studies. J. Nucl. Med. 2007; 48(1): 158-167.


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