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Novel Non-Congeneric Derivatives of the Choline Kinase Alpha Inhibitor ICL-CCIC-0019

Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics

Cancer Imaging Centre, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London SW7 2BX, UK
Russell H. Morgan Department of Radiology and Radiological Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
Author to whom correspondence should be addressed.
Academic Editor: Luisa Carlota Lopez-Cara
Pharmaceutics 2021, 13(8), 1246;
Received: 7 July 2021 / Revised: 5 August 2021 / Accepted: 6 August 2021 / Published: 12 August 2021
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 [18F]fluoromethyl-[1,2-2H4]-choline ([18F]-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, [18F]-D4-FCH, were investigated: 18F-D4-FCH import, CHKA phosphorylation activity, and the efflux of [18F]-D4-FCH and its phosphorylated product [18F]-D4-FCHP. The effects of hypoxia on [18F]-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 [18F]-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 [18F]-D4-FCH and [18F]-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. View Full-Text
Keywords: choline kinase; hypoxia; efflux choline kinase; hypoxia; efflux
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MDPI and ACS Style

Li, Y.; Inglese, M.; Dubash, S.; Barnes, C.; Brickute, D.; Braga, M.C.; Wang, N.; Beckley, A.; Heinzmann, K.; Allott, L.; Lu, H.; Chen, C.; Fu, R.; Carroll, L.; Aboagye, E.O. Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics. Pharmaceutics 2021, 13, 1246.

AMA Style

Li Y, Inglese M, Dubash S, Barnes C, Brickute D, Braga MC, Wang N, Beckley A, Heinzmann K, Allott L, Lu H, Chen C, Fu R, Carroll L, Aboagye EO. Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics. Pharmaceutics. 2021; 13(8):1246.

Chicago/Turabian Style

Li, Yunqing, Marianna Inglese, Suraiya Dubash, Chris Barnes, Diana Brickute, Marta C. Braga, Ning Wang, Alice Beckley, Kathrin Heinzmann, Louis Allott, Haonan Lu, Cen Chen, Ruisi Fu, Laurence Carroll, and Eric O. Aboagye. 2021. "Consideration of Metabolite Efflux in Radiolabelled Choline Kinetics" Pharmaceutics 13, no. 8: 1246.

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