Fluorine Radioisotopes; Membrane Transport Proteins; Blood-Brain Barrier; Fluorine Radioisotopes/chemistry; Membrane Transport Proteins/metabolism; Positron-Emission Tomography/methods; Positron-Emission Tomography; Molecular Medicine; Drug Discovery
Abstract :
[en] Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.
Disciplines :
Chemistry Radiology, nuclear medicine & imaging
Author, co-author :
Sander, Kerstin; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Galante, Eva; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Gendron, Thibault ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique-nucléaire ; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Yiannaki, Elena; ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K
Patel, Niral; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Kalber, Tammy L; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Badar, Adam; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Robson, Mathew; ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Johnson, Sean P; ∥Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Bauer, Florian; ⊥Department of Medicinal Chemistry, Faculty of Life Sciences, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria
Mairinger, Severin; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Stanek, Johann; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Wanek, Thomas; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Kuntner, Claudia; #Health and Environment Department, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria
Kottke, Tim; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Weizel, Lilia; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Dickens, David; ○The Wolfson Centre for Personalised Medicine, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Block A Waterhouse Buildings, 1-5 Brownlow Street, Liverpool L69 3GL, U.K
Erlandsson, Kjell; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Hutton, Brian F; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K
Lythgoe, Mark F; §Centre for Advanced Biomedical Imaging, University College London, 72 Huntley Street, London WC1E 6DD, U.K
Stark, Holger; ∇Institute of Pharmaceutical Chemistry, Biocenter, Johann Wolfgang Goethe University, Max-von-Laue-Strasse 9, 60438 Frankfurt am Main, Germany
Langer, Oliver; ●Department of Clinical Pharmacology, Medical University of Vienna, Waehringer-Guertel 18-20, A-1090 Vienna, Austria
Koepp, Matthias; ◆Department of Clinical and Experimental Epilepsy, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, U.K
Årstad, Erik; †Institute of Nuclear Medicine, University College London, 235 Euston Road, T5, London NW1 2BU, U.K ; ‡Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K
FP7 - 201380 - EURIPIDES - EUropean Research initiative to develop Imaging Probes for early In-vivo Diagnosis and Evaluation of response to therapeutic Substances
Miller, D. S. Regulation of ABC transporters at the blood-brain barrier Clin. Pharmacol. Ther. 2015, 97, 395-403 10.1002/cpt.64
Seelig, A. A general pattern for substrate recognition by P-glycoprotein Eur. J. Biochem. 1998, 251, 252-261 10.1046/j.1432-1327.1998.2510252.x
Penzotti, J. E.; Lamb, M. L.; Evensen, E.; Grootenhuis, P. D. J. A computational ensemble pharmacophore model for identifying substrates of P-glycoprotein J. Med. Chem. 2002, 45, 1737-1740 10.1021/jm0255062
International Transporter Consortium. Membrane transporters in drug development Nat. Rev. Drug Discovery 2010, 9, 215-236 10.1038/nrd3028
Robey, R. W.; Massey, P. R.; Amiri-Kordestani, L.; Bates, S. E. ABC transporters: unvalidated therapeutic targets in cancer and the CNS Anti-Cancer Agents Med. Chem. 2010, 10, 625-633 10.2174/187152010794473957
Agarwal, S.; Elmquist, W. F. Insight into the cooperation of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier: a case study examining sorafenib efflux clearance Mol. Pharmaceutics 2012, 9, 678-684 10.1021/mp200465c
de Vries, N. A.; Zhao, J.; Kroon, E.; Buckle, T.; Beijnen, J. H.; van Tellingen, O. P-glycoprotein and breast cancer resistance protein: two dominant transporters working together in limiting the brain penetration of topotecan Clin. Cancer Res. 2007, 13, 6440-6449 10.1158/1078-0432.CCR-07-1335
Mittapalli, R. K.; Vaidhyanathan, S.; Sane, R.; Elmquist, W. F. Impact of P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) on the brain distribution of a novel BRAF inhibitor: vemurafenib (PLX4032) J. Pharmacol. Exp. Ther. 2012, 342, 33-40 10.1124/jpet.112.192195
Kubota, H.; Ishihara, H.; Langmann, T.; Schmitz, G.; Stieger, B.; Wieser, H.-G.; Yonekawa, Y.; Frei, K. Distribution and functional activity of P-glycoprotein and multidrug resistance-associated proteins in human brain microvascular endothelial cells in hippocampal sclerosis Epilepsy Res. 2006, 68, 213-228 10.1016/j.eplepsyres.2005.11.011
Feldmann, M.; Asselin, M.-C.; Liu, J.; Wang, S.; McMahon, A.; Anton-Rodriguez, J.; Walker, M.; Symms, M.; Brown, G.; Hinz, R.; Matthews, J.; Bauer, M.; Langer, O.; Thom, M.; Jones, T.; Vollmar, C.; Duncan, J. S.; Sisodiya, S. M.; Koepp, M. J. P-glycoprotein expression and function in patients with temporal lobe epilepsy: a case-control study Lancet Neurol. 2013, 12, 777-785 10.1016/S1474-4422(13)70109-1
Xiong, H.; Callaghan, D.; Jones, A.; Bai, J.; Rasquinha, I.; Smith, C.; Pei, K.; Walker, D.; Lue, L. F.; Stanimirovic, D.; Zhang, W. ABCG2 is upregulated in Alzheimer's brain with cerebral amyloid angiopathy and may act as a gatekeeper at the blood-brain barrier for Abeta(1-40) peptides J. Neurosci. 2009, 29, 5463-5475 10.1523/JNEUROSCI.5103-08.2009
Krishnamurthy, P.; Ross, D. D.; Nakanishi, T.; Bailey-Dell, K.; Zhou, S.; Mercer, K. E.; Sarkadi, B.; Sorrentino, B. P.; Schuetz, J. D. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme J. Biol. Chem. 2004, 279, 24218-24225 10.1074/jbc.M313599200
Natarajan, K.; Xie, Y.; Baer, M. R.; Ross, D. D. Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance Biochem. Pharmacol. 2012, 83, 1084-1103 10.1016/j.bcp.2012.01.002
Hermann, D. M.; Kilic, E.; Spudich, A.; Kramer, S. D.; Wunderli-Allenspach, H.; Bassetti, C. L. Role of drug efflux carriers in the healthy and diseased brain Ann. Neurol. 2006, 60, 489-498 10.1002/ana.21012
Löscher, W.; Potschka, H. Drug resistance in brain diseases and the role of drug efflux transporters Nat. Rev. Neurosci. 2005, 6, 591-602 10.1038/nrn1728
Urquhart, B. L.; Kim, R. B. Blood-brain barrier transporters and response to CNS-active drugs Eur. J. Clin. Pharmacol. 2009, 65, 1063-1070 10.1007/s00228-009-0714-8
Löscher, W.; Potschka, H. Role of drug efflux transporters in the brain for drug disposition and treatment of brain diseases Prog. Neurobiol. 2005, 76, 22-76 10.1016/j.pneurobio.2005.04.006
Müllauer, J.; Karch, R.; Bankstahl, J. P.; Bankstahl, M.; Stanek, J.; Wanek, T.; Mairinger, S.; Müller, M.; Löscher, W.; Langer, O.; Kuntner, C. Assessment of cerebral P-glycoprotein expression and function with PET by combined [11C]inhibitor and [11C]substrate scans in rats Nucl. Med. Biol. 2013, 40, 755-763 10.1016/j.nucmedbio.2013.05.005
Kannan, P.; Telu, S.; Shukla, S.; Ambudkar, S. V.; Pike, V. W.; Halldin, C.; Gottesman, M. M.; Innis, R. B.; Hall, M. D. The "specific" P-glycoprotein inhibitor tariquidar is also a substrate and an inhibitor for breast cancer resistance protein (BCRP/ABCG2) ACS Chem. Neurosci. 2011, 2, 82-89 10.1021/cn100078a
Bankstahl, J. P.; Bankstahl, M.; Römermann, K.; Wanek, T.; Stanek, J.; Windhorst, A. D.; Fedrowitz, M.; Erker, T.; Müller, M.; Löscher, W.; Langer, O.; Kuntner, C. 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 Metab. Dispos. 2013, 41, 754-462 10.1124/dmd.112.049148
Colabufo, N. A.; Berardi, F.; Cantore, M.; Contino, M.; Inglese, C.; Niso, M.; Perrone, R. Perspectives of P-glycoprotein modulating agents in oncology and neurodegenerative diseases: pharmaceutical, biological, and diagnostic potentials J. Med. Chem. 2010, 53, 1883-1897 10.1021/jm900743c
Kannan, P.; John, C.; Zoghbi, S. S.; Halldin, C.; Gottesman, M. M.; Innis, R. B.; Hall, M. D. Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications Clin. Pharmacol. Ther. 2009, 86, 368-377 10.1038/clpt.2009.138
Mairinger, S.; Erker, T.; Muller, M.; Langer, O. PET and SPECT radiotracers to assess function and expression of ABC transporters in vivo Curr. Drug Metab. 2011, 12, 774-792 10.2174/138920011798356980
Okamura, T.; Kikuchi, T.; Okada, M.; Toramatsu, C.; Fukushi, K.; Takei, M.; Irie, T. Noninvasive and quantitative assessment of the function of multidrug resistance-associated protein 1 in the living brain J. Cereb. Blood Flow Metab. 2009, 29, 504-511 10.1038/jcbfm.2008.135
Galante, E.; Okamura, T.; Sander, K.; Kikuchi, T.; Okada, M.; Zhang, M. R.; Robson, M.; Badar, A.; Lythgoe, M.; Koepp, M.; Arstad, E. Development of purine-derived 18F-labeled pro-drug tracers for imaging of MRP1 activity with PET J. Med. Chem. 2014, 57, 1023-1032 10.1021/jm401764a
Pavan, B.; Dalpiaz, A.; Ciliberti, N.; Biondi, C.; Manfredini, S.; Vertuani, S. Progress in drug delivery to the central nervous system by the prodrug approach Molecules 2008, 13, 1035-65 10.3390/molecules13051035
Zhao, R.; Kalvass, J. C.; Yanni, S. B.; Bridges, A. S.; Pollack, G. M. Fexofenadine brain exposure and the influence of blood-brain barrier P-glycoprotein after fexofenadine and terfenadine administration Drug Metab. Dispos. 2009, 37, 529-535 10.1124/dmd.107.019893
Chen, C.; Hanson, E.; Watson, J. W.; Lee, J. S. P-glycoprotein limits the brain penetration of nonsedating but not sedating H1-antagonists Drug Metab. Dispos. 2003, 31, 312-318 10.1124/dmd.31.3.312
Doan, K. M.; Wring, S. A.; Shampine, L. J.; Jordan, K. H.; Bishop, J. P.; Kratz, J.; Yang, E.; Serabjit-Singh, C. J.; Adkison, K. K.; Polli, J. W. Steady-state brain concentrations of antihistamines in rats: interplay of membrane permeability, P-glycoprotein efflux and plasma protein binding Pharmacology 2004, 72, 92-98 10.1159/000079137
Obradovic, T.; Dobson, G. G.; Shingaki, T.; Kungu, T.; Hidalgo, I. J. Assessment of the first and second generation antihistamines brain penetration and role of P-glycoprotein Pharm. Res. 2007, 24, 318-327 10.1007/s11095-006-9149-4
Renwick, A. G. The metabolism of antihistamines and drug interactions: the role of cytochrome P450 enzymes Clin. Exp. Allergy 1999, 29 (Suppl. 3) 116-124 10.1046/j.1365-2222.1999.0290s3116.x
Sander, K.; Kottke, T.; Hoffend, C.; Walter, M.; Weizel, L.; Camelin, J. C.; Ligneau, X.; Schneider, E. H.; Seifert, R.; Schwartz, J. C.; Stark, H. First metal-containing histamine H3 receptor ligands Org. Lett. 2010, 12, 2578-2581 10.1021/ol100419y
Omura, K.; Swern, D. Oxidation of alcohols by "activated" dimethyl sulfoxide. a preparative, steric and mechanistic study Tetrahedron 1978, 34, 1651-1660 10.1016/0040-4020(78)80197-5
Shiuey, S. J.; Partridge, J. J.; Uskokovic, M. R. Triply convergent synthesis of 1α,25-dihydroxy-24(R)-fluorocholecalciferol J. Org. Chem. 1988, 53, 1040-1046 10.1021/jo00240a021
Ohta, A.; Sawamoto, D.; Jayasundera, K. P.; Kinoshita, H.; Inomata, K. Efficient synthesis of B- and C-rings components of phycobilin derivatives for structure/function analysis of phytochrome Chem. Lett. 2000, 29, 492-493 10.1246/cl.2000.492
Tamura, S.; Kaneko, M.; Shiomi, A.; Yang, G. M.; Yamaura, T.; Murakami, N. Unprecedented NES non-antagonistic inhibitor for nuclear export of Rev from Sida cordifolia Bioorg. Med. Chem. Lett. 2010, 20, 1837-1839 10.1016/j.bmcl.2010.01.165
Riss, P. J.; Hummerich, R.; Schloss, P. Synthesis and monoamine uptake inhibition of conformationally constrained 2β-carbomethoxy-3β-phenyl tropanes Org. Biomol. Chem. 2009, 7, 2688-2698 10.1039/b902863c
Iradier, F.; Arrayás, R. G.; Carretero, J. C. Synthesis of medium-sized cyclic amines by selective ring cleavage of sulfonylated bicyclic amines Org. Lett. 2001, 3, 2957-2960 10.1021/ol0162163
Zhou, J.; Zhang, A.; Klass, T.; Johnson, K. M.; Wang, C. Z.; Ye, Y. P.; Kozikowski, A. P. Biaryl analogues of conformationally constrained tricyclic tropanes as potent and selective norepinephrine reuptake inhibitors: synthesis and evaluation of their uptake inhibition at monoamine transporter sites J. Med. Chem. 2003, 46, 1997-2007 10.1021/jm020596w
Proschak, E.; Sander, K.; Zettl, H.; Tanrikulu, Y.; Rau, O.; Schneider, P.; Schubert-Zsilavecz, M.; Stark, H.; Schneider, G. From molecular shape to potent bioactive agents II: fragment-based de novo design ChemMedChem 2009, 4, 45-48 10.1002/cmdc.200800314
Laine, D. I.; McCleland, B.; Thomas, S.; Neipp, C.; Underwood, B.; Dufour, J.; Widdowson, K. L.; Palovich, M. R.; Blaney, F. E.; Foley, J. J.; Webb, E. F.; Luttmann, M. A.; Burman, M.; Belmonte, K.; Salmon, M. Discovery of novel 1-azoniabicyclo[2.2.2]octane muscarinic acetylcholine receptor antagonists J. Med. Chem. 2009, 52, 2493-2505 10.1021/jm801601v
Uto, Y.; Ogata, T.; Kiyotsuka, Y.; Ueno, Y.; Miyazawa, Y.; Kurata, H.; Deguchi, T.; Watanabe, N.; Konishi, M.; Okuyama, R.; Kurikawa, N.; Takagi, T.; Wakimoto, S.; Ohsumi, J. Novel benzoylpiperidine-based stearoyl-CoA desaturase-1 inhibitors: Identification of 6-[4-(2-methylbenzoyl)piperidin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-2-pyridin-3-ylethyl)amide and its plasma triglyceride-lowering effects in Zucker fatty rats Bioorg. Med. Chem. Lett. 2010, 20, 341-345 10.1016/j.bmcl.2009.10.101
Tredwell, M.; Gouverneur, V. 18F Labeling of arenes Angew. Chem., Int. Ed. 2012, 51, 11426-11437 10.1002/anie.201204687
Brooks, A. F.; Topczewski, J. J.; Ichiishi, N.; Sanford, M. S.; Scott, P. J. Late-stage [18F]fluorination: new solutions to old problems Chem. Sci. 2014, 5, 4545-4553 10.1039/C4SC02099E
Mu, L.; Fischer, C. R.; Holland, J. P.; Becaud, J.; Schubiger, P. A.; Schibli, R.; Ametamey, S. M.; Graham, K.; Stellfeld, T.; Dinkelborg, L. M.; Lehmann, L. 18F-Radiolabeling of aromatic compounds using triarylsulfonium salts Eur. J. Org. Chem. 2012, 2012, 889-892 10.1002/ejoc.201101730
Sander, K.; Gendron, T.; Yiannaki, E.; Cybulska, K.; Kalber, T. L.; Lythgoe, M. F.; Arstad, E. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18 Sci. Rep. 2015, 5, 9941 10.1038/srep09941
Zhu, M.; Jalalian, N.; Olofsson, B. One-pot synthesis of diaryliodonium salts using toluenesulfonic acid: a fast entry to electron-rich diaryliodonium tosylates and triflates Synlett 2008, 4, 592-596 10.1055/s-2008-1032050
Kazmierczak, P.; Skulski, L. Oxidative anion metatheses in diaryliodonium iodides and chlorides Bull. Chem. Soc. Jpn. 1997, 70, 219-224 10.1246/bcsj.70.219
Schwab, D.; Fischer, H.; Tabatabaei, A.; Poli, S.; Huwyler, J. Comparison of in vitro P-glycoprotein screening assays: recommendations for their use in drug discovery J. Med. Chem. 2003, 46, 1716-1725 10.1021/jm021012t
Kuntner, C.; Bankstahl, J. P.; Bankstahl, M.; Stanek, J.; Wanek, T.; Stundner, G.; Karch, R.; Brauner, R.; Meier, M.; Ding, X.; Müller, M.; Löscher, W.; Langer, O. 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 10.1007/s00259-009-1332-5
Gunn, R. N.; Gunn, S. R.; Cunningham, V. J. Positron emission tomography compartmental models J. Cereb. Blood Flow Metab. 2001, 21, 635-652 10.1097/00004647-200106000-00002
Matsson, P.; Pedersen, J. M.; Norinder, U.; Bergström, C. A. S.; Artursson, P. Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs Pharm. Res. 2009, 26, 1816-1831 10.1007/s11095-009-9896-0
Martignoni, M.; Groothuis, G. M.; de Kanter, R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction Expert Opin. Drug Metab. Toxicol. 2006, 2, 875-894 10.1517/17425255.2.6.875
Warren, M. S.; Zerangue, N.; Woodford, K.; Roberts, L. M.; Tate, E. H.; Feng, B.; Li, C.; Feuerstein, T. J.; Gibbs, J.; Smith, B.; de Morais, S. M.; Dower, W. J.; Koller, K. J. Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human Pharmacol. Res. 2009, 59, 404-413 10.1016/j.phrs.2009.02.007
Syvänen, S.; Lindhe, Ö.; Palner, M.; Kornum, B. R.; Rahman, O.; Långström, B.; Knudsen, G. M.; Hammarlund-Udenaes, M. Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport Drug Metab. Dispos. 2009, 37, 635-643 10.1124/dmd.108.024745
Walsh, D. A.; Franzyshen, S. K.; Yanni, J. M. Synthesis and antiallergy activity of 4-(Diarylhydroxymethyl)-1-[3-(aryloxy)propyl]piperidines and structurally related compounds J. Med. Chem. 1989, 32, 105-118 10.1021/jm00121a022
Takahashi, S.; Hongo, Y.; Tsukagoshi, Y.; Koshino, H. Structural determination of Montanacin D by total synthesis Org. Lett. 2008, 10, 4223-4226 10.1021/ol801576z
Smit, M. J.; Timmerman, H.; Hijzelendoorn, J. C.; Fukui, H.; Leurs, R. Regulation of the human histamine H1 receptor stably expressed in Chinese hamster ovary cells Br. J. Pharmacol. 1996, 117, 1071-1080 10.1111/j.1476-5381.1996.tb16699.x
