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The Assay of Enzyme Activity by Positron Emission Tomography

  • Paul Cumming
  • Neil Vasdev
Protocol
Part of the Neuromethods book series (NM, volume 71)

Abstract

In a relatively small number of instances, the activity in brain of specific enzymes can be measured with positron emission tomography (PET) using radioactive enzyme substrates in conjunction with compartmental modeling. Thus, the trapping of [11C]-labeled amino acids in brain protein was an early application of PET, which has found particular use in the detection of brain tumors. The most successful PET agent remains the glucose analog [18F]-fluoro-deoxyglucose (FDG), which is trapped in brain as FDG-phosphate, at a rate determined by the local activity of the hexokinase enzyme. The integrity of nigrostriatal dopamine innervations can be assessed with the DOPA decarboxylase tracer [18F]-fluoro-l-DOPA (FDOPA), whereas the rate of serotonin synthesis has been measured in PET studies with α-[14C]-methyl-l-tryptophan. Monoamine oxidase, uniquely, can be assessed in PET studies with suicide substrates such as l-[11C]-deprenyl, where the rate of trapping in living tissue is a function of the local catalytic activity of MAO-B. However, the abundance of MAO-A is most conveniently assessed with [11C]-harmine and other competitor ligands, which bind reversibly to the enzyme. [11C]-PMP and a number of other substrates for acetylcholine esterase have been developed, based on the production in situ of a nondiffusible hydrolysis product. The activity of P-glycoprotein in the blood–brain barrier can be assessed only indirectly, by virtue of increased influx to brain of labeled substrates, following administration of P-glycoprotein inhibitors. Positron-emitting inhibitors of phosphodiesterase enzymes have been described, which should herald the eventual development of a much wider array of tracers targeting signal transduction pathways. Cell proliferation can be detected with [11C]-thymidine and synthetic nucleosides. Very recently, it has become possible to measure the abundance in brain of aromatase, which catalyzes the synthesis of estrogen. In general, the net influx of an enzyme substrate from blood to brain is calculated by linear graphical analysis, whereas individual steps in the non-uptake process can be estimated by compartmental analysis. When trapping of a PET tracer is catalyzed by the enzymatic step, the magnitude of the corresponding rate constant (k 3; min−1) ranges from the lowest useful limit of 0.01 min−1 (α-[14C]-methyl-l-tryptophan) to >0.1 min−1 (l-[11C]-deprenyl, [11C]PMP). Quantification is problematic at the lower end of this range due to low specific signal and also at the high end due to blood flow limiting effects.

Key words

Positron emission tomography Methionine FDG FDOPA DOPA decarboxylase Monoamine oxidase Serotonin Acetylcholinesterase Phosphodiesterase Proliferation Aromatase 

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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Paul Cumming
    • 1
  • Neil Vasdev
    • 2
  1. 1.Department of Nuclear MedicineLudwig-Maximilians-Universität MünchenMünchenGermany
  2. 2.Division of Nuclear Medicine and Molecular ImagingMassachusetts General Hospital, Harvard Medical SchoolBostonUSA

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