Interaction of 11C-Tariquidar and 11C-Elacridar with P-Glycoprotein and Breast Cancer Resistance Protein at the Human Blood-Brain Barrier

被引:44
作者
Bauer, Martin [1 ]
Karch, Rudolf [2 ]
Zeitlingerl, Markus [1 ]
Stanek, Johann [1 ,3 ]
Philippe, Cecile [1 ,4 ]
Wadsak, Wolfgang [4 ]
Mitterhauser, Markus [4 ]
Jaeger, Walter [5 ]
Haslacher, Helmuth [6 ]
Mueller, Markus [1 ]
Langer, Oliver [1 ,3 ]
机构
[1] Med Univ Vienna, Dept Clin Pharmacol, A-1090 Vienna, Austria
[2] Med Univ Vienna, Ctr Med Stat Informat & Intelligent Syst, A-1090 Vienna, Austria
[3] AIT Austrian Inst Technol GmbH, Hlth & Environm Dept, Seibersdof, Austria
[4] Med Univ Vienna, Dept Nucl Med, Vienna, Austria
[5] Univ Vienna, Dept Clin Pharm & Diagnost, Vienna, Austria
[6] Med Univ Vienna, Dept Lab Med, Vienna, Austria
基金
奥地利科学基金会;
关键词
P-glycoprotein; breast cancer resistance protein; blood-brain barrier; C-11-tariquidar; C-11-elacridar; POSITRON-EMISSION-TOMOGRAPHY; IN-VIVO; TRANSPORTERS; TARIQUIDAR; PHARMACOKINETICS; RADIOTRACER; INHIBITION; SUBSTRATE; PROTOCOL; PET;
D O I
10.2967/jnumed.112.118232
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The adenosine triphosphate-binding cassette transporters P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) are 2 major gatekeepers at the blood brain barrier (BBB) that restrict brain distribution of several clinically used drugs. In this study, we investigated the suitability of the radiolabeled Pgp/BCRP inhibitors C-11-tariquidar and C-11-elacridar to assess Pgp density in the human brain with PET. Methods: Healthy subjects underwent a first PET scan of 120-min duration with either C-11-tariquidar (n = 6) or C-11-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-C-11-verapamil. During scan 1 (at 60 min after radiotracer injection), unlabeled tariquidar (3 mg/kg) was intravenously administered. Data were analyzed using 1-tissue 2-rate-constant (1T2K) and 2-tissue 4-rate-constant (2T4K) compartment models and either metabolite-corrected or uncorrected arterial input functions. Results: After injection of C-11-tariquidar or C-11-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (similar to 0.1 standardized uptake value), with slow washout. In response to tariquidar injection, a moderate but statistically significant rise in brain PET signal was observed for C-11-tariquidar (+27% +/- 15%, P = 0.014, paired t test) and C-11-elacridar (+21% +/- 15%, P = 0.014) without changes in plasma activity concentrations. Low levels of radiolabeled metabolites (<25%) were detected in plasma up to 60 min after injection of C-11-tariquidar or C-11-elacridar. The 2T4K model provided better data fits than the 1T2K model. Model outcome parameters were similar when metabolite-corrected or uncorrected input functions were used. There was no significant correlation between distribution volumes of C-11-tariquidar or C-11-elacridar and distribution volumes of (R)-C-11-verapamil in different brain regions. Conclusion: The in vivo behavior of C-11-tariquidar and C-11-elacridar was consistent with that of dual Pgp/BCRP substrates. Both tracers were unable to visualize cerebral Pgp density, most likely because of insufficiently high binding affinities in relation to the low density of Pgp in human brain (similar to 1.3 nM). Despite their inability to visualize Pgp density, C-11-tariquidar and 11C-elacridar may find use as a new class of radiotracers to study the interplay of Pgp and BCRP at the human BBB in limiting brain uptake of dual substrates.
引用
收藏
页码:1181 / 1187
页数:7
相关论文
共 30 条
[21]  
Miillauer J, 2013, NUCL MED BIOL
[22]   Blood-brain barrier biology and methodology [J].
Pardridge, WM .
JOURNAL OF NEUROVIROLOGY, 1999, 5 (06) :556-569
[23]   Simultaneous analysis of MDR1 C3435T, G2677T/A, and C1236T genotypes by multiplexed mutagenically separated PCR [J].
Sunder-Plassmann, R ;
Rieger, S ;
Endler, G ;
Brunner, M ;
Müller, M ;
Mannhalter, C .
CLINICAL CHEMISTRY AND LABORATORY MEDICINE, 2005, 43 (02) :192-194
[24]   Duration and degree of cyclosporin induced P-glycoprotein inhibition in the rat blood-brain barrier can be studied with PET [J].
Syvanen, Stina ;
Blomquist, Gunnar ;
Sprycha, Margareta ;
Hoglund, A. Urban ;
Roman, Magnus ;
Eriksson, Olof ;
Hammarlund-Udenaes, Margareta ;
Langstrom, Bengt ;
Bergstrom, Mats .
NEUROIMAGE, 2006, 32 (03) :1134-1141
[25]   Targeting multidrug resistance in cancer [J].
Szakács, G ;
Paterson, JK ;
Ludwig, JA ;
Booth-Genthe, C ;
Gottesman, MM .
NATURE REVIEWS DRUG DISCOVERY, 2006, 5 (03) :219-234
[26]   Quantitative targeted absolute proteomics of human blood-brain barrier transporters and receptors [J].
Uchida, Yasuo ;
Ohtsuki, Sumio ;
Katsukura, Yuki ;
Ikeda, Chiemi ;
Suzuki, Takashi ;
Kamiie, Junichi ;
Terasaki, Tetsuya .
JOURNAL OF NEUROCHEMISTRY, 2011, 117 (02) :333-345
[27]  
Wagner CC, 2009, J NUCL MED, V50, P1954, DOI 10.2967/jnumed.109.063289
[28]   A novel PET protocol for visualization of breast cancer resistance protein function at the blood-brain barrier [J].
Wanek, Thomas ;
Kuntner, Claudia ;
Bankstahl, Jens P. ;
Mairinger, Severin ;
Bankstahl, Marion ;
Stanek, Johann ;
Sauberer, Michael ;
Filip, Thomas ;
Erker, Thomas ;
Mueller, Markus ;
Loescher, Wolfgang ;
Langer, Oliver .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 2012, 32 (11) :2002-2011
[29]   A comparative small-animal PET evaluation of [11C]tariquidar, [11C]elacridar and (R)-[11C]verapamil for detection of P-glycoprotein-expressing murine breast cancer [J].
Wanek, Thomas ;
Kuntner, Claudia ;
Bankstahl, Jens P. ;
Bankstahl, Marion ;
Stanek, Johann ;
Sauberer, Michael ;
Mairinger, Severin ;
Strommer, Sabine ;
Wacheck, Volker ;
Loescher, Wolfgang ;
Erker, Thomas ;
Mueller, Markus ;
Langer, Oliver .
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2012, 39 (01) :149-159
[30]   Determination of P-glycoprotein inhibition by excipients and their combinations using an integrated high-throughput process [J].
Wang, SW ;
Monagle, J ;
McNulty, C ;
Putnam, D ;
Chen, HM .
JOURNAL OF PHARMACEUTICAL SCIENCES, 2004, 93 (11) :2755-2767