Mike Kondrasho @Mike-Kondrasho

Short description: there seems to be a lot of evidence that [11C]-alpha-Me-tryptophan (AMT, not to be confused with 1-methyl or N-methyl tryptophan) PET imaging is correlated with metabolism of tryptophan via kynurenine pathway. However, has anyone shown it biochemically except for this paper in Theranostics http://www.thno.org/v07p1524.htm ?

Long description: I am new to the field and there is a lot of articles, but that is what I understood so far.

1. Tryptophan is metabolized in mammals via 2 major pathways - a) by hydroxylation of benzene ring leading to 5-hydroxytryptophan and later to serotonin (serotonin pathway); b) by oxidation of heteroaromatic part leading to N-formyl-kynurenine (NFK), then kynurenine (KYN) and kynurenic acid (KYNA) (kynurenine pathway).

2. On the second pathway the first step (Try=>NFK) is performed by 3 enzymes IDO1, IDO2 and TDO, out of which the first one is the most important.

3. alpha-Me-tryptophan (AMT) is an analog of tryptophan which is used a lot in PET imaging. Long time ago it was demonstrated that AMT is oxidized to corresponding metabolites via serotonine pathway, which can be isolated both in vitro and in vivo. (see e.g. this article Article α Methyltryptophan: effects on cerebral monooxygenases in vi...

) Hence, when it started to be used as a PET tracer, initially it was believed that the tracer accumulation is related to serotonin pathway activity.

4. Later more and more evidence was gathered that the uptake of AMT is also correlated with the kynurenine pathway metabolism. However, all of this evidence is biomedical in nature (e.g. we see a lot of cells with this enzyme and the tracer accumulates in this cell), but not biochemical. I cannot find the corresponding molecular interactions to be demonstrated yet (see exception in p6). Even though in some papers I see a phrase like "AMT is a known inhibitor of IDO" without proper references given.

5. If AMT is a substrate for the corresponding kynurenine enzymes, the corresponding metabolites can be isolated in vivo or in vitro. If it is an inhibitor it can be shown by some inhibition experiment. I cannot find it being done.

6. There is one paper where enzyme essay with AMT and IDO1 enzyme is performed and authors claim that this compound is a substrate for IDO-1, almost as good as the natural substrate - tryptophan (http://www.thno.org/v07p1524.htm). However, it comes in contradiction with earlier study (Article N 1 -Fluoroalkyltryptophan Analogues: Synthesis and in vitro...

) as well as my own results. In my in vitro experiment I can see that it is clearly not a substrate or at least it is converted >100 slower than tryptophan.

7. I cannot get access to an earlier review (Southan et al Med. Chem. Res., 1996, 6, 5, 343-352). But from the abstract it seems to state that if you modify tryptophan around the amino-acid residue, you get compounds which have low activity as substrates and inhibitors for IDO (not specified 1 or 2), and AMT is included in this review. Does someone have a full text, maybe it could help?

8. I ran one inhibition test with IDO1 and it seems that AMT is not an inhibitor either or an extremely weak inhibitor for IDO1. Though, I cannot vouch for this result just yet, needs to be repeated.

My own conclusion is that AMT does not interact with IDO1. Maybe it is a substrate or an inhibitor for IDO2 or TDO, but it is not proven either. However, I am afraid that I missed some important article that clarifies this question. Maybe someone who is an expert can help me out: is there a clear explanation of relation between AMT and kynurenine pathway on a molecular level?