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 tracers 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 tracers 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. Tracers for brain 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.

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. 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 tracer development phase. Metabolic profiles are species dependent.


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References

Amini N, Nakao R, Schou M, Halldin C. Identification of PET radiometabolites by cytochrome P450, UHPLC/Q-ToF-MS and fast radio-LC: applied to the PET radioligands [11C]flumazenil, [18F]FE-PE2I, and [11C]PBR28. Anal Bioanal Chem. 2013; 405: 1303-1310.

Giron MC, Portolan S, Bin A, Mazzi U, Cutler CS. Cytochrome P450 and radiopharmaceutical metabolism. Q J Nucl Med Mol Imaging 2008; 52(3): 254-266.

Gourand F, Amini N, Jia Z, Stone-Elander S, Guilloteau D, Barré L, Halldin C. [11C]MADAM used as a model for understanding the radiometabolism of diphenyl sulfide radioligands for positron emission tomography (PET). PLoS ONE 2015; 10(9): e0137160.

Ma Y, Kiesewetter DO, Lang L, Gu D, Chen X. Applications of LC-MS in PET radioligand development and metabolic elucidation. Curr Drug Metab. 2010; 11(6): 483-493.

Osman S, Lundkvist C, Pike VW, Halldin C, McCarron JA, Swahn CG, Farde L, Ginovart N, Luthra SK, Gunn RN, Bench CJ, Sargent PA, Grasby PM. Characterisation of the appearance of radioactive metabolites in monkey and human plasma from the 5-HT1A receptor radioligand, [carbonyl-11C]WAY-100635 - explanation of high signal contrast in PET and an aid to biomathematical modelling. Nucl Med Biol. 1998; 25(3): 215-223.

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.



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Created at: 2015-12-14
Updated at: 2015-12-15
Written by: Vesa Oikonen