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Measurement of BuChE activity with
[¹¹C]MP4B PET

Model

1-[¹¹C]methyl-4-piperidinyl n-butyrate ([¹¹C]MP4B or [¹¹C]nBMP or [¹¹C]BMP) was suggested as an optimal tracer for measuring butyrylcholinesterase (BuChE) activity in the brain (Snyder et al., 2001) and was further validated by Roivainen et al. (2004).

For the quantification of BuChE activity, a three-compartment (two-tissue compartment) model is applied. The rate constant k₃ represents the rate of hydrolysis of [¹¹C]MP4B by BuChE. The diffusion of radioactive metabolite of [¹¹C]MP4B through the blood-brain-barrier is assumed negligible during the PET study, thus k₄=0.

Kuhl et al. (2006) estimated K₁, k₃ and V_B for [¹¹C]MP4B pixel-by-pixel, constraining K₁/k₂ to a value determined as the mean estimate across cortical regions of all subjects from the unconstrained fits (Koeppe et al. 1999; Kuhl et al., 1999).

Analysis method in TPC

Pre-processing plasma input

Make sure that you have all the necessary data files:

On-line sampler data file
Dynamic PET image file from this study
This file is used to correct for possible start time mismatch between PET and blood sampling. Normally, both were started simultaneously, and in that case you do not need the dynamic image file yet.
Count-rate curve
Plasma curve from manual sampling
Plasma metabolite data file

Then, follow the instructions in http://www.turkupetcentre.net/analysis/doc/tracer_input.html. Note that for [C-11]MP4B:

Conversion from blood to plasma or from plasma to blood is not necessary, because blood and plasma TACs are similar
Hill-type function should be used to fit the fractions of parent tracer in plasma
In the time delay correction, do not use the whole data that was collected but only the first 10 minutes after injection. Time delay must be fitted between PET count-rate curve and metabolite corrected plasma TAC, but remember to correct simulatenously also the total plasma TAC.

Image processing

PET images are summed over frames, coregistered with MRI, and regions of interest are defined.

For regional analysis, TACs are calculated from the dynamic PET image.

Before proceeding, make sure that both the plasma and tissue data are in the same calibration units (preferably kBq/ml) and that the time unit is min. Image data from HR+ and PET-CT may originally be in units Bq/ml.

Regional BuChE activity (k₃)

After all the previous steps have been done succesfully, the enzyme activity k₃ can be calculated using programs lhsol or fitk3. Program fitk3 allows constraining K₁/k₂ to a predetermined value and fitting the vascular volume fraction. If K₁/k₂ is not constrained, you should consider reporting (K₁/k₂)*k₃ as an index of enzyme activity, instead of k₃.

Examples:

lhsol -k3 ua2826ap_comb_pure.delay.kbq ua2826dy1.dft 999 ua2826k3.res ua2826k3fit.dat

fitk3 -i=constraints.set ua2826ap_comb_pure.delay.kbq ua2826ab_comb.delay.kbq ua2826dy1.dft 999 ua2826k3.res ua2826k3fit.dat

Note that you must use the delay fitted (filename usually contains *.delay.*) and metabolite corrected plasma curves.

If necessary, there are tools for processing the result file further.

Butyrylcholinesterase activity maps

To be added later.

References:

Kikuchi T, Zhang MR, Ikota N, Fukushi K, Okamura T, Suzuki K, Arano Y, Irie T. N-[¹⁸F]fluoroethylpiperidin-4-ylmethyl butyrate: a novel radiotracer of quantifying brain butyrylcholinesterase activity by positron emission tomography. Bioorg. Med. Chem. Lett. 2004; 14(8): 1927-1930.

Koeppe RA, Frey KA, Snyder SE, Meyer P, Kilbourn MR, Kuhl DE. Kinetic modeling of N-[¹¹C]Methylpiperidin-4-yl propionate: Alternatives for analysis of an irreversible positron emission tomography tracer for measurement of acetylcholinesterase activity in human brain. J. Cereb. Blood Flow Metabol. 1999; 19: 1150-1163.

Kuhl DE, Koeppe RA, Minoshima S, Snyder SE, Ficaro EP, Foster NL, Frey KA, Kilbourn MR. In vivo mapping of cerebral acetylcholinesterase activity in aging and Alzheimer's disease. Neurology 1999; 52(4): 691-699.

Kuhl DE, Koeppe RA, Snyder SE, Minoshima S, Frey KA, Kilbourn MR. In vivo butyrylcholinesterase activity is not increased in Alzheimer's disease synapses. Ann. Neurol. 2006; 59: 13-20.

Roivainen A, Rinne J, Virta J, Järvenpää T, Salomäki S, Yu M, Någren K. Biodistribution and blood metabolism of 1-¹¹C-methyl-4-piperidinyl n-butyrate in humans: an imaging agent for in vivo assessment of butyrylcholinesterase activity with PET. J. Nucl. Med. 2004; 45: 2032-2039.

Snyder SE, Gunupudi N, Sherman PS, Butch ER, Skaddan MB, Kilbourn MR, Koeppe RA, Kuhl DE. Radiolabeled cholinesterase substrates: in vitro methods for determining structure-activity relationships and identification of a positron emission tomography radiopharmaceutical for in vivo measurement of butyrylcholinesterase activity. J. Cereb. Blood Flow Metab. 2001; 21:132-143.

Measurement of BuChE activity with [11C]MP4B PET