Labelled alpha-methyl-L-tryptophan as a tracer for the study of the brain serotonergic system

Abstract

The alpha-methyl-L-trypotophan (alpha-MTrp) method for the study of the brain serotonergic system is based on the fact that labelled alpha-MTrp is taken up by and, in part, retained in the brain, and this retention (trapping) is proportional to brain serotonin (5-HT) synthesis. A 3-compartment model is proposed in which the plasma, the precursor and irreversible pools are mathematically distinct compartments. The irreversible compartment is assumed to be the one in which the tracer is trapped. By definition, the tracer from the irreversible compartment does not exchange directly with the plasma compartment. The rate at which labelled alpha-MTrp is trapped is converted to the rate of 5-HT synthesis by dividing it by a conversion factor, called the lumped constant, and multiplying it by the plasma-free tryptophan concentration. Our results revealed that brain 5-HT synthesis can be influenced by the extraneuronal concentration of 5-HT and that, generally, the influence is not uniform throughout the brain. They also suggest that brain trapping of labelled alpha-MTrp relates to 5-HT synthesis. The proposed procedure for converting the rate at which labelled alpha-MTrp is trapped to brain 5-HT synthesis rates is based on measurements that suggest that plasma-free Trp relates to brain 5-HT synthesis. However, as with all biological models, there is likely room for improvement in our approach.

Fig. 1: Schematic representation of the brain compartmental structure used in the modelling of labelled α -methyl-L-tryptophan. The rate constants are assumed to be first-order rate constant and have units of min^-1 except K₁^α (in mL/g per min), which is the product of the first-order rate constant k₁^α (per min) and the plasma volume (in mL/g) from which tracer is transferred into the brain precursor pool. The k₂^α is the constant for the movement of the tracer from the precursor pool to plasma, and k₃^α is the rate constant for the movement of the tracer from the precursor pool to the brain irreversible pool.

Fig. 2: A comparison between 2- and 3-compartment fits to the experimental data obtained in rats. The rats, each represented by one point on the graph, were killed at different times after tracer injection. The y axis represents distribution volume of the tracer (DV, in mL/g) obtained by dividing tissue tracer radioactivity with the plasma radioactivity measured at the end of experiment, and the x axis (theta, min) represents an integral of the plasma radioactivity divided with the plasma radioactivity at the end of experiment. A statistical evaluation of residues indicated that the 3-compartment model provided a significantly (F = 26, p < 10^–4) better fit to the experimental data than the 2-compartment model.

Fig. 3: A comparison between 2- and 3-compartment fits obtained in a human scanned for 90 min after tracer injection. The axes are defined as in Fig. 2. The 3-compartment fit was significantly better (F = 120, p < 10^-6]. The fitting was done with the SAAM II program (SAAM Institute, University of Washington, Seattle, WA).