Imaging of ABC transporters at the blood-brain barrier with positron emission tomography
Date: June 05 2013
Presenter(s): Oliver Langer, PhD
Imaging of ABC transporters at the blood-brain barrier with positron emission tomography
Webinar presented on June 5th, 2013 by Oliver Langer, PhD (AIT Austrian Institute of Technology GmbH and Medical University of Vienna, Austria)
Summary of the presentation:
Adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp, ABCB1) and breast cancer resistance protein (BCRP, ABCG2), are expressed in various organs and tissues and transport a wide range of structurally diverse molecules thereby exerting a considerable impact on drug absorption, distribution and excretion. Changes in ABC transporter expression and function are thought to be implicated in various diseases, such as cancer, epilepsy, Alzheimer’s and Parkinson’s disease. The non-invasive nuclear imaging method positron emission tomography (PET) allows for assessing the density or function of molecular targets in vivo by externally monitoring the tissue distribution of intravenously administered target-selective radiotracers. The availability of PET radiotracers to measure ABC transporter function or expression could be useful in personalized medicine to preselect epilepsy or cancer patients with increased ABC transporter activity who may benefit from treatment with ABC transporter modulating drugs. In addition, PET imaging with radiolabelled drugs is a very powerful approach to assess drug-drug interactions in vivo in human subjects. To date two different kinds of PET imaging probes have been described to measure ABC transporters in vivo: i) radiolabelled transporter substrates ii) radiolabelled transporter inhibitors. The design of new imaging probes to visualize efflux transporters is inter alia complicated by the overlapping substrate recognition pattern of different ABC transporter types. The present talk will summarize the speaker’s experience in the PET visualization of ABC transporters in animal disease models (epilepsy, cancer) and in humans.
Literature References provided by Oliver Langer, PhD
1. Kannan P, John C, Zoghbi SS, et al. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin Pharmacol Ther. 2009;86:368-377.
2. Sasongko L, Link JM, Muzi M, et al. Imaging P-glycoprotein transport activity at the human blood-brain barrier with positron emission tomography. Clin Pharmacol Ther. 2005;77:503-514.
3. Kreisl WC, Liow JS, Kimura N, et al. P-glycoprotein function at the blood-brain barrier in humans can be quantified with the substrate radiotracer 11C-N-desmethyl-loperamide. J Nucl Med. 2010;51:559-566.
4. Kuntner C, Bankstahl JP, Bankstahl M, et al. Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET. Eur J Nucl Med Mol Imaging. 2010;37:942-953.
5. Bauer M, Zeitlinger M, Karch R, et al. Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data. Clin Pharmacol Ther. 2012;91:227-233.
6. Kalvass JC, Polli JW, Bourdet DL, et al. Why clinical inhibition of efflux transport at the blood-brain barrier is unlikely:the ITC evidence-based position. Clin Pharmacol Ther. 2013.
7. Brandt C, Bethmann K, Gastens AM, Löscher W. The multidrug transporter hypothesis of drug resistance in epilepsy: Proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis. 2006;24:202-211.
8. Bankstahl JP, Bankstahl M, Kuntner C, et al. A novel PET imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood-brain barrier. J Neurosci. 2011;31:8803-8811.
9. Feldmann M, Asselin M-C, Liu J, et al. P-glycoprotein function and expression in temporal lobe epilepsy: a case-control study. Lancet Neurology. 2013;in press.
10. van Assema DM, Lubberink M, Bauer M, et al. Blood-brain barrier P-glycoprotein function in Alzheimer's disease. Brain. 2012;135:181-189.
11. Wanek T, Kuntner C, Bankstahl JP, et al. A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer. Eur J Nucl Med Mol Imaging. 2012;39:149-159.
12. Wanek T, Kuntner C, Bankstahl JP, et al. A novel PET protocol for visualization of breast cancer resistance protein function at the blood-brain barrier. J Cereb Blood Flow Metab. 2012;32:2002-2011.
13. Bankstahl JP, Bankstahl M, Römermann K, et al. Tariquidar and elacridar are dose-dependently transported by p-glycoprotein and bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study Drug Metabol Dispos. 2013;41:754-762.
14. Kannan P, Pike VW, Halldin C, et al. Factors that limit positron emission tomography imaging of p-gycoprotein density at the blood-brain barrier. Molecular Pharmaceutics. 2013;in press.
About the presenter:
LANGER, Oliver, PhD
Senior Scientist Health & Environment Department Biomedical Systems , AIT Austrian Institute of Technology GmbH Seibersdorf, Austria
Biography
Oliver Langer was born in 1971 in Vienna, Austria. He studied pharmacy at the University of Vienna and graduated with a Master’s degree in 1995. He obtained his PhD degree at the Karolinska Institute in Stockholm, Sweden in 2000, where he specialized in the development of radiotracers for the imaging of neurotransmitter systems with positron emission tomography (PET). During his PhD studies he spent 3 years as a research fellow at the Service Hospitalier Frédéric Joliot (French Atomic Energy Commission, CEA) in Orsay, France. Since 2002 he has been employed at the Department of Clinical Pharmacology at the Medical University of Vienna (Austria), where he became Associate Professor (“Privatdozent”) in Radiopharmaceutical Chemistry in 2006. In 2010, he became Senior Scientist at Austrian Institute of Technology in Seibersdorf, which is Austria’s largest non-university research organization. In his research, he uses preclinical and clinical PET to address different questions related to drug disposition and pharmacodynamics.
