Consideration of metabolite efflux in radiolabelled choline kinetics

Yunqing Li, Marianna Inglese, Suraiya Dubash, Chris Barnes, Diana Brickute, Marta Costa Braga, Ning Wang, Alice Beckley, Kathrin Heinzmann, Louis Allott, Haonan Lu, Cen Chen, Ruisi Fu, Laurence Carroll, Eric O. Aboagye

Research output: Contribution to journalArticlepeer-review


Hypoxia is a complex microenvironmental condition known to regulate choline kinase α (CHKA) activity and choline transport through transcription factor hypoxia-inducible factor-1α (HIF-1α) and, therefore, may confound the uptake of choline radiotracer [18 F]fluoromethyl-[1,2-2 H4 ]-choline ([18 F]-D4-FCH). The aim of this study was to investigate how hypoxia affects the choline radiotracer dynamics. Three underlying mechanisms by which hypoxia could potentially alter the uptake of the choline radiotracer, [18 F]-D4-FCH, were investigated:18 F-D4-FCH import, CHKA phos-phorylation activity, and the efflux of [18 F]-D4-FCH and its phosphorylated product [18 F]-D4-FCHP. The effects of hypoxia on [18 F]-D4-FCH uptake were studied in CHKA-overexpressing cell lines of prostate cancer, PC-3, and breast cancer MDA-MB-231 cells. The mechanisms of radiotracer efflux were assessed by the cell uptake and immunofluorescence in vitro and examined in vivo (n = 24). The mathematical modelling methodology was further developed to verify the efflux hypothesis using [18 F]-D4-FCH dynamic PET scans from non-small cell lung cancer (NSCLC) patients (n = 17). We report a novel finding involving the export of phosphorylated [18 F]-D4-FCH and [18 F]-D4-FCHP via HIF-1α-responsive efflux transporters, including ABCB4, when the HIF-1α level is augmented. This is supported by a graphical analysis of human data with a compartmental model (M2T6k + k5 ) that accounts for the efflux. Hypoxia/HIF-1α increases the efflux of phosphorylated radiolabelled choline species, thus supporting the consideration of efflux in the modelling of radiotracer dynamics.

Original languageEnglish (US)
Article number1246
Issue number8
StatePublished - Aug 2021


  • Choline kinase
  • Efflux
  • Hypoxia

ASJC Scopus subject areas

  • Pharmaceutical Science


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