Radioactive metabolites of PET tracers

PET scanner can measure the total amount of radioactivity in tissue, but it does not provide information on the chemical form of molecule(s) in which the radioactive label was attached at the time of the PET scan. PET radiopharmaceuticals are metabolized in the body, and some of the products will carry the radioactive label. Some of these reactions are planned, for example the phosphorylation and subsequent trapping of [18F]FDG, but usually the PET radiopharmaceuticals are metabolized into undesirable radioactive compounds that will confound the quantification. Radioactive metabolites in the plasma samples can be corrected, but the metabolites in the tissue must be accounted for in the analysis model. Radiopharmaceuticals developed for brain PET studies are by design molecules which do not metabolize into radioactive products that could cross the blood-brain barrier (Ma et al., 2010), although there are important exceptions to this rule, such as [18F]FDOPA.

Deuterium labelling alters the pharmacokinetic properties of pharmaceuticals, and has been used to improve metabolic resistance of PET radiopharmaceuticals (Klenner et al., 2021).

Identification of metabolites

Radioactive metabolites must be identified for two purposes: First, for the determination of the fractions of parent tracer in plasma, and secondly, for ruling out or appropriately accounting for the tissue uptake of the radioactive metabolites.

Circulating metabolites of PET radioligands are mainly produced in the liver. Metabolic profiles are species dependent. Hepatocytes and hepatic microsome preparations are therefore used to study the metabolism in vitro (Giron et al., 2008; Amini et al., 2013), already during the development phase of radiopharmaceutical. Micropatterned cocultures of primary human hepatocytes (PHH) increase the predictability of drug metabolism (Lauschke et al., 2019).

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Saba W, Peyronneau M-A, Dollé F, Goutal S, Bottlaender M, Valette H. Difficulties in dopamine transporter radioligand PET analysis: the example of LBT-999 using [18F] and [11C] labelling. Part I: PET studies. Nucl Med Biol. 2012; 39: 227-233. doi: 10.1016/j.nucmedbio.2011.08.003.

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Updated at: 2022-01-02
Created at: 2015-12-14
Written by: Vesa Oikonen