PET imaging of protein synthesis rate

Protein synthesis rate (PSR) can be quantified in vivo with labelled L-amino-acids or amino-acid analogues, using PET and adequate analysis methods.

Different proteins contain amino-acids in different proportions, and the relative rates of incorporation into proteins and other metabolic pathways are also variable. Therefore different amino-acid tracers will provide different estimates of PSR. From PET image data it is not possible to discriminate the protein-bound radioactivity from radioactivity bound to other molecules, and therefore the optimal amino acid tracer should have minimal metabolism to non-proteins (Vaalburg et al., 1992, Paans et al., 1996). Production of extracellular matrix proteins can be an important driver for increased amino acid uptake during inflammation and tissue remodelling.

Labelling amino acids with 11C in the carboxylic position increases the specificity of net uptake to PSR, because metabolism through decarboxylation leads to [11C]CO2, which in turn is rapidly cleared from the tissue (Phelps et al., 1984). If amino-acid is labelled in the methyl group, the methyl group may be transferred to many small- and large molecular weight molecules, especially in case of L-[methyl-11C]methionine (Phelps et al., 1984; Ishiwata et al., 1988a). Indeed, the uptake of L-[methyl-11C]methionine and L-2-[18F]fluorotyrosine have been shown to represent mostly amino-acid transport or phospholipid synthesis rather than protein synthesis rate, while L-[1-11C]leucine and L-[1-11C]tyrosine represent PSR (Ishiwata et al., 1988b, 1993 and 1996). Careful modelling may still provide reliable PSR in skeletal muscle with L-[methyl-11C]methionine (Hsu et al., 1996; Fischman et al., 1998). Compartmental models for L-[1-11C]leucine brain PET have been developed (Schmidt et al., 2005; Sundaram et al., 2006) and the models can be used in small animal studies (Bochicchio et al., 2023).

Transport of amino acids into cells is usually not the rate-limiting step in peripheral tissues and tumours, but in the brain the uptake may be limited by the capacity of the carrier system or partial saturation by physiological amino-acids in plasma (Vaalburg et al., 1992). L-alanine, L-tyrosine, and L-methionine have the highest brain uptake indices (Vaalburg et al., 1992).

In oncological studies the main aim is usually not to measure protein synthesis per se, but cell growth in general. Incorporation of labelled amino-acid in other metabolic pathways than protein synthesis is not a drawback in such studies (Paans et al., 1996). 18F-labelled glutamine analogues are not metabolized in the TCA cycle, but are incorporated into proteins (Yang et al., 2017), and can be used assess transporter (ASCT2) activity or protein synthesis rate.

D-amino acids are not used by mammalian cells, and could therefore be used for infection imaging.


See also:


Literature

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Updated at: 2023-05-11
Created at: 2015-01-26
Written by: Vesa Oikonen