Measurement of BuChE activity with [11C]MP4B
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 VB 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
PET images are summed over frames, coregistered with MRI, and regions of interest are defined as usual. For regional analysis, ROI TACs are calculated from the dynamic PET image. TACs should be weighted before fitting.
Pre-processing plasma input
The necessary data files:
- On-line blood sampler data file
- Optionally dynamic PET image file from this study:
This file is used to correct for possible start time mismatch between PET and ABSS. 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 parent fractions
Then, follow the instructions on input data processing. 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 can be used to fit the fractions of parent tracer in plasma; use default weighting
- Correct the input data for time delay. Do not use all of the data that was collected but only the first 10 minutes after tracer administration. Time delay must be fitted between PET count-rate curve and metabolite corrected plasma TAC, but remember to correct simultaneously also the total plasma TAC.
Before proceeding, make sure that both the plasma and tissue data are in the same calibration units.
Regional BuChE activity (k3)
After all the previous steps have been done successfully, the enzyme activity k3 can be calculated using programs lhsol or, preferably, 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.
Example for using fitk3:
fitk3 -lim=constraints.set -svg=ua2826k3.svg ua2826apc_delay.kbq ua2826ab_comb.delay.kbq ua2826dy1.dft 999 ua2826k3.res
Note that you must use the delay fitted (file name usually contains *_delay.*) and metabolite corrected plasma curves.
To be added later.
Darvesh S. Butyrylcholinesterase radioligands to image Alzheimer’s disease brain. Chem Biol Interact. 2013; 203(1): 354-357.
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.
Virta JR, Tolvanen T, Någren K, Brück A, Roivainen A, Rinne JO. 1-11C-methyl-4-piperidinyl-N-butyrate radiation dosimetry in humans by dynamic organ-speciﬁc evaluation. J Nucl Med. 2008; 49:347–353.
Created at: 2006-09-18
Updated at: 2014-05-29
Written by: Vesa Oikonen