Membrane transporters in PET imaging
Cellular membranes form a barrier to most of organic and inorganic solutes. Specific transporter proteins enable strictly regulated transport of solutes across the membranes, down or against their concentration gradient. Transport against the concentration gradient ("active" transport) requires energy, which is obtained by exploiting ion gradients or from subsequent ATP turnover. For reviews on transporters, see the literature below. In the absence of transporter, membrane permeability is correlated with the solutes oil/water partition coefficient. Lipid bilayer membranes are heterogeneous, with higher lipophilicity in the centre of the bilayer, which is taken into account in inhomogeneous solubility-diffusion model.
PET radiopharmaceuticals are being used and actively developed for studying the function and localization of transporters. Transporters are not only important as targets of functional PET imaging, but transporters indirectly affect the usability of PET radiopharmaceuticals for studying other functions, since transporters are needed for the radiopharmaceuticals to reach their targets across epithelial barriers (such as endothelial barriers, especially BBB) and in intracellular organelles. Transporters are also involved in the excretion of PET radiopharmaceuticals from the body, and the distribution of their radioactive metabolites. Labelled drug molecules can be used to study the effect of transporter systems on drug biodistribution and transporter-mediated drug-drug interaction.
- Fatty acid transport proteins
- Folate transporters
- Copper transporter 1
- Monocarboxylate transporters
- Amino-acid transporters
- Dopamine transporter
- Noradrenaline transporter
- Serotonin transporter
- Endothelial barrier
Alexander SP, Kelly E, Marrion N, Peters JA, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Southan C, Davies JA, CGTP Collaborators. The Concise Guide to PHARMACOLOGY 2015/16: Transporters. Br J Pharmacol. 2015; 172(24): 6110-6202. doi: 10.1111/bph.13355.
Endres CJ, Hsiao P, Chung FS, Unadkat JD. The role of transporters in drug interactions. Eur J Pharm Sci. 2006; 27: 501-517. doi: 10.1016/j.ejps.2005.11.002.
International Transporter Consortium; Giacomini KM, Huang SM, Tweedie DJ, Benet LZ, Brouwer KL, Chu X, Dahlin A, Evers R, Fischer V, Hillgren KM, Hoffmaster KA, Ishikawa T, Keppler D, Kim RB, Lee CA, Niemi M, Polli JW, Sugiyama Y, Swaan PW, Ware JA, Wright SH, Yee SW, Zamek-Gliszczynski MJ, Zhang L. Membrane transporters in drug development. Nat Rev Drug Discov. 2010; 9(3): 215-236. doi: 10.1038/nrd3028.
Kilbourn MR. Small molecule PET tracers for transporter imaging. Semin Nucl Med. 2017; 47(5): 536-552. doi: 10.1053/j.semnuclmed.2017.05.005.
Kusuhara H. Imaging in the study of membrane transporters. Clin Pharmacol Ther. 2013; 94(1): 33-36. doi: 10.1038/clpt.2013.85.
Langer O. Use of PET imaging to evaluate transporter-mediated drug-drug interactions. J Clin Pharmacol. 2016; 56(Suppl 7): S143-S156. doi: 10.1002/jcph.722.
Mann A, Semenenko I, Meir M, Eyal S. Molecular imaging of membrane transporters' activity in cancer: a picture is worth a thousand tubes. AAPS J. 2015; 17(4): 788-801. doi: 10.1208/s12248-015-9752-6.
Nakanishi T. Drug transporters as targets for cancer chemotherapy. Cancer Genomics Proteomics 2007; 4(3): 241-254. PMID: 17878527.
Pizzagalli MD, Bensimon A, Superti-Furga G. A guide to plasma membrane solute carrier proteins. FEBS J. 2021; 288(9): 2784-2835. doi: 10.1111/febs.15531.
Shinoda W. Permeability across lipid membranes. Biochim Biophys Acta 2016; 1858: 2254-2265. doi: 10.1016/j.bbamem.2016.03.032.
Shitara Y, Horie T, Sugiyama Y. Transporters as a determinant of drug clearance and tissue distribution. Eur J Pharm Sci. 2006; 27(5): 425-446. doi: 10.1016/j.ejps.2005.12.003.
Steffansen B, Brodin B, Nielsen CU (eds.): Molecular Biopharmaceutics. Pharmaceutical Press, 2010, ISBN: 978-0-85369-722-0.
Tournier N, Stieger B, Langer O. Imaging techniques to study drug transporter function in vivo. Pharmacol Ther. 2018; 189: 104-122. doi: 10.1016/j.pharmthera.2018.04.006.
Wulkersdorfer B, Wanek T, Bauer M, Zeitlinger M, Müller M, Langer O. Using positron emission tomography to study transporter-mediated drug-drug interactions in tissues. Clin Pharmacol Ther. 2014; 96(2): 206-213. doi: 10.1038/clpt.2014.70.
Xu H, Martinoia E, Szabo I. Organellar channels and transporters. Cell Calcium 2015; 58(1): 1-10. doi: 10.1016/j.ceca.2015.02.006.
You G, Morris ME (eds.): Drug Transporters - Molecular Characterization and Role in Drug Disposition, 2nd ed. Wiley, 2014, ISBN: 978-1-118-48993-2.
Updated at: 2023-01-12
Created at: 2015-08-17
Written by: Vesa Oikonen