Oliver Langer

AIT Austrian Institute of Technology, Wien, Vienna, Austria

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Publications (103)306.49 Total impact

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    ABSTRACT: Transport of 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) by the multidrug efflux transporters P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) at the blood-brain barrier (BBB) may confound the interpretation of [(18)F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [(18)F]FDG in vivo by performing [(18)F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [(18)F]FDG brain distribution after transporter inhibition. Dynamic small-animal PET experiments (60min) were performed with [(18)F]FDG in groups of wild-type and transporter knockout mice (Abcb1a/b((-/-)), Abcg2((-/-)) and Abcb1a/b((-/-))Abcg2((-/-))) and in wild-type rats without and with i.v. pretreatment with the known ABCB1 inhibitor tariquidar (15mg/kg, given at 2h before PET). Blood was sampled from animals from the orbital sinus vein at the end of the PET scans and measured in a gamma counter. Brain uptake of [(18)F]FDG was expressed as the brain-to-blood radioactivity concentration ratio in the last PET time frame (Kb,brain). Kb,brain values of [(18)F]FDG were not significantly different between different mouse types both without and with tariquidar pretreatment. The blood-to-brain transfer rate constant of [(18)F]FDG was significantly lower in tariquidar-treated as compared with vehicle-treated rats (0.350±0.025mL/min/g versus 0.416±0.024mL/min/g, p=0.026, paired t-test) but Kb,brain values were not significantly different between both rat groups. Our results show that [(18)F]FDG is not transported by Abcb1 at the mouse and rat BBB in vivo. In addition we found no evidence for Abcg2 transport of [(18)F]FDG at the mouse BBB. Our findings imply that functional activity of ABCB1 and ABCG2 at the BBB does not need to be taken into account when interpreting brain [(18)F]FDG PET data. Copyright © 2015. Published by Elsevier Inc.
    Nuclear Medicine and Biology 03/2015; DOI:10.1016/j.nucmedbio.2015.03.004 · 2.41 Impact Factor
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    ABSTRACT: We transferred the previously published manual synthesis of [(18)F]ciprofloxacin (decay-corrected RCY: 5.5±1.0%) to an automated synthesis module (TRACERlab(TM) FXFDG, GE Healthcare) and observed a strong decrease in RCY (0.4±0.4%). When replacing the standard 15-mL glassy carbon reactor of the synthesis module with a 3-mL V-shaped borosilicate glass reactor a considerable improvement in RCY was observed. [(18)F]Ciprofloxacin was obtained in a RCY of 2.7±1.4% (n=23) with a specific activity at EOS of 1.4±0.5GBq/µmol in a synthesis time of 160min. Copyright © 2015 Elsevier Ltd. All rights reserved.
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    ABSTRACT: As P-glycoprotein (Pgp) inhibition at the blood-brain barrier (BBB) after administration of a single dose of tariquidar is transient, we performed positron emission tomography (PET) scans with the Pgp substrate (R)-[(11)C]verapamil in five healthy volunteers during continuous intravenous tariquidar infusion. Total distribution volume (VT) of (R)-[(11)C]verapamil in whole-brain gray matter increased by 273±78% relative to baseline scans without tariquidar, which was higher than previously reported VT increases. During tariquidar infusion whole-brain VT was comparable to VT in the pituitary gland, a region not protected by the BBB, which suggested that we were approaching complete Pgp inhibition at the human BBB.Journal of Cerebral Blood Flow & Metabolism advance online publication, 11 February 2015; doi:10.1038/jcbfm.2015.19.
    Journal of Cerebral Blood Flow & Metabolism 02/2015; DOI:10.1038/jcbfm.2015.19 · 5.34 Impact Factor
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    ABSTRACT: The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [(18)F]FE@SUPPY. Rats were injected with [(18)F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [(18)F]FE@SUPPY and [(18)F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [(18)F]FE@SUPPY in human and rat plasma was also evaluated. [(18)F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [(18)F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [(18)F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [(18)F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [(18)F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [(18)F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [(18)F]FE@SUPPY was stable in human plasma. Selective and significant tracer uptake of [(18)F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [(18)F]FE@SUPPY in "humanized animal models". In conclusion, preclinical evaluation points to the suitability of [(18)F]FE@SUPPY as an A3R PET tracer in humans.
    European journal of nuclear medicine and molecular imaging 01/2015; 42(5). DOI:10.1007/s00259-014-2976-3 · 5.22 Impact Factor
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    Jens Pahnke, Oliver Langer, Markus Krohn
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    ABSTRACT: Much has been said about the increasing number of demented patients and the main risk factor ‘age’. Frustratingly, we do not know the precise pattern and all modulating factors that provoke the pathologic changes in the brains of affected elderly. We have to diagnose early to be able to stop the progression of diseases that irreversibly destroy brain substance. Familiar AD cases have mislead some researchers for almost 20 years, which has unfortunately narrowed the scientific understanding and has, thus, lead to insufficient funding of independent approaches. Therefore, basic researchers hardly have been able to develop causative treatments and clinicians still do not have access to prognostic and early diagnostic tools. During the recent years it became clear that insufficient Aβ export, physiologically facilitated by the ABC transporter superfamily at the brain’s barriers, plays a fundamental role in disease initiation and progression. Furthermore, export mechanisms that are deficient in affected elderly are new targets for activation and, thus, treatment, but ideally also for prevention. In sporadic AD disturbed clearance of β-amyloid from the brain is so far the most important factor for its accumulation in the parenchyma and vessel walls. Here, we review findings about the contribution of ABC transporters and of the perivascular drainage/glymphatic system on β-amyloid clearance. We highlight their potential value for innovative early diagnostics using PET and describe recently described, effective ABC transporter-targeting agents as potential causative treatment for neurodegenerative proteopathies/dementias.
    Neurobiology of Disease 12/2014; DOI:10.1016/j.nbd.2014.04.001 · 5.20 Impact Factor
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    ABSTRACT: This report is a summary of the presentations of a symposium sponsored by the American Society for Pharmacology and Toxicology (ASPET) held April 26-30 at Experimental Biology 2014 in San Diego, CA. The presentations focused on the role of transporters in imaging in health and disease and on assessing transporter function in vivo. Imaging is an import diagnostic tool in clinics and is a novel tool to visualize in vivo the function of transporters. Many imaging substrates and endogenous markers for organ function are organic anions. In this symposium, the bile salt transporter sodium taurocholate cotransporting polypeptide (NTCP) and the liver organic anion transporting polypeptides (OATPs) as well as the renal organic anion transporters (OATs) were addressed in detail. E.g., OATPs mediate transport of contrast agents used for magnetic resonance imaging of the liver or transport agents used for hepatobiliary scintigraphy, while OATs transport substances used in renography. In addition, the multidrug resistance transporter 1 (MDR1 or P-gp), which is the most important gate keeper in epithelial or endothelial barriers for preventing the entry of potentially harmful substances into organs was addressed. Novel substrates suitable for positron emission tomography (PET) allow studying such transporters at the blood brain barrier or while mediating uptake of drugs into hepatocytes and, importantly, PET tracers allow now also renography. Finally, quantitative data on transporter expression in human organs allow the development of improved physiologically based pharmacokinetic (PBPK) models for drug disposition. Hence, the combined effort using novel substrates for in vivo visualization of transporters and quantification of transporters will lead to a deeper understanding of transporter function in disease and allow development of novel PBPK models for disease states.
    Drug metabolism and disposition: the biological fate of chemicals 09/2014; DOI:10.1124/dmd.114.059873 · 3.33 Impact Factor
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    ABSTRACT: To study the functional activity of the multidrug efflux transporter P-glycoprotein (Pgp) at the blood-brain barrier of patients with temporal lobe epilepsy using (R)-[(11)C]verapamil (VPM)-PET before and after temporal lobe surgery to assess whether postoperative changes in seizure frequency and antiepileptic drug load are associated with changes in Pgp function.
    Neurology 09/2014; DOI:10.1212/WNL.0000000000000858 · 8.30 Impact Factor
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    Clinical Pharmacology &#38 Therapeutics 03/2014; DOI:10.1038/clpt.2014.70 · 7.39 Impact Factor
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    ABSTRACT: Aim: The partial volume effect (PVE) significantly affects quantitative accuracy in PET. In this study we used a micro-hollow sphere phantom filled with 18F, 11C or 68Ga to evaluate different partial volume correction methods (PVC). Additionally, phantom data were applied on rat brain scans to evaluate PVC methods on in vivo datasets. Methods: The four spheres (7.81, 6.17, 5.02, 3.90 mm inner diameter) and the background region were filled to give sphere-to-background (sph/bg) activity ratios of 20 : 1, 10 : 1, 5 : 1 and 2 : 1. Two different acquisition and reconstruction protocols and three radionuclides were evaluated using a small animal PET scanner. From the obtained images the recovery coefficients (RC) and contrast recovery coefficients (CRC) for the different sph/bg ratios were calculated. Three methods for PVC were evaluated: a RC based, a CRC based and a volume of interest (VOI) based method. The most suitable PVC methods were applied to in vivo rat brain data. Results: RCs were shown to be dependent on the radionuclide used, with the highest values for 18F, followed by 11C and 68Ga. The calculated mean CRCs were generally lower than the corresponding mean RCs. Application of the different PVC methods to rat brain data led to a strong increase in time-activity curves for the smallest brain region (entorhinal cortex), whereas the lowest increase was obtained for the largest brain region (cerebellum). Conclusion: This study was able to show the importance and impact of PVE and the limitations of several PVC methods when performing quantitative measurements in small structures.
    Nuklearmedizin 12/2013; 52(6):250-261. DOI:10.3413/Nukmed-0578-13-04 · 1.67 Impact Factor
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    ABSTRACT: Positron emission tomography (PET) with [(11)C]verapamil, either in racemic form or in form of the (R)-enantiomer, has been used to measure the functional activity of the adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) at the blood-brain barrier (BBB). There is some evidence in literature that verapamil inhibits two other ABC transporters expressed at the BBB, i.e. multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). However, previous data were obtained with micromolar concentrations of verapamil and do not necessarily reflect the transporter selectivity of verapamil at nanomolar concentrations, which are relevant for PET experiments. The aim of this study was to assess the selectivity of verapamil, in nanomolar concentrations, for Pgp over MRP1 and BCRP. Concentration equilibrium transport assays were performed with [(3)H]verapamil (5nM) in cell lines expressing murine or human Pgp, human MRP1, and murine Bcrp1 or human BCRP. Paired PET scans were performed with (R)-[(11)C]verapamil in female FVB/N (wild-type), Mrp1((-/-)), Mdr1a/b((-/-)), Bcrp1((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice, before and after Pgp inhibition with 15mg/kg tariquidar. In vitro transport experiments exclusively showed directed transport of [(3)H]verapamil in Mdr1a- and MDR1-overexpressing cells which could be inhibited by tariquidar (0.5μM). In PET scans acquired before tariquidar administration, brain-to-blood ratio (Kb,brain) of (R)-[(11)C]verapamil was low in wild-type (1.3±0.1), Mrp1((-/-)) (1.4±0.1) and Bcrp1((-/-)) mice (1.8±0.1) and high in Mdr1a/b((-/-)) (6.9±0.8) and Mdr1a/b((-/-))Bcrp1((-/-)) mice (7.9±0.5). In PET scans after tariquidar administration, Kb,brain was significantly increased in Pgp-expressing mice (wild-type: 5.0±0.3-fold, Mrp1((-/-)): 3.2±0.6-fold, Bcrp1((-/-)): 4.3±0.1-fold) but not in Pgp knockout mice (Mdr1a/b((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-))). Our combined in vitro and in vivo data demonstrate that verapamil, in nanomolar concentrations, is selectively transported by Pgp and not by MRP1 and BCRP at the BBB, which supports the use of (R)-[(11)C]verapamil or racemic [(11)C]verapamil as PET tracers of cerebral Pgp function.
    Nuclear Medicine and Biology 07/2013; 40(7). DOI:10.1016/j.nucmedbio.2013.05.012 · 2.41 Impact Factor
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    ABSTRACT: 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 (11)C-tariquidar and (11)C-elacridar to assess Pgp density in the human brain with PET. Healthy subjects underwent a first PET scan of 120-min duration with either (11)C-tariquidar (n = 6) or (11)C-elacridar (n = 5) followed by a second PET scan of 60-min duration with (R)-(11)C-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. After injection of (11)C-tariquidar or (11)C-elacridar, the brain PET signal corrected for radioactivity in the vasculature was low (∼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 (11)C-tariquidar (+27% ± 15%, P = 0.014, paired t test) and (11)C-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 (11)C-tariquidar or (11)C-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 (11)C-tariquidar or (11)C-elacridar and distribution volumes of (R)-(11)C-verapamil in different brain regions. The in vivo behavior of (11)C-tariquidar and (11)C-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 (∼1.3 nM). Despite their inability to visualize Pgp density, (11)C-tariquidar and (11)C-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.
    Journal of Nuclear Medicine 07/2013; 54(8). DOI:10.2967/jnumed.112.118232 · 5.56 Impact Factor
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    ABSTRACT: Studies in rodent models of epilepsy suggest that multidrug efflux transporters at the blood-brain barrier, such as P-glycoprotein, might contribute to pharmacoresistance by reducing target-site concentrations of antiepileptic drugs. We assessed P-glycoprotein activity in vivo in patients with temporal lobe epilepsy. We selected 16 patients with pharmacoresistant temporal lobe epilepsy who had seizures despite treatment with at least two antiepileptic drugs, eight patients who had been seizure-free on antiepileptic drugs for at least a year after 3 or more years of active temporal lobe epilepsy, and 17 healthy controls. All participants had a baseline PET scan with the P-glycoprotein substrate (R)-[(11)C]verapamil. Pharmacoresistant patients and healthy controls then received a 30-min infusion of the P-glycoprotein-inhibitor tariquidar followed by another (R)-[(11)C]verapamil PET scan 60 min later. Seizure-free patients had a second scan on the same day, but without tariquidar infusion. Voxel-by-voxel, we calculated the (R)-[(11)C]verapamil plasma-to-brain transport rate constant, K1 (mL/min/cm(3)). Low baseline K1 and attenuated K1 increases after tariquidar correspond to high P-glycoprotein activity. Between October, 2008, and November, 2011, we completed (R)-[(11)C]verapamil PET studies in 14 pharmacoresistant patients, eight seizure-free patients, and 13 healthy controls. Voxel-based analysis revealed that pharmacoresistant patients had lower baseline K1, corresponding to higher baseline P-glycoprotein activity, than seizure-free patients in ipsilateral amygdala (0·031 vs 0·036 mL/min/cm(3); p=0·014), bilateral parahippocampus (0·032 vs 0·037; p<0·0001), fusiform gyrus (0·036 vs 0·041; p<0·0001), inferior temporal gyrus (0·035 vs 0·041; p<0·0001), and middle temporal gyrus (0·038 vs 0·044; p<0·0001). Higher P-glycoprotein activity was associated with higher seizure frequency in whole-brain grey matter (p=0·016) and the hippocampus (p=0·029). In healthy controls, we noted a 56·8% increase of whole-brain K1 after 2 mg/kg tariquidar, and 57·9% for 3 mg/kg; in patients with pharmacoresistant temporal lobe epilepsy, whole-brain K1 increased by only 21·9% for 2 mg/kg and 42·6% after 3 mg/kg. This difference in tariquidar response was most pronounced in the sclerotic hippocampus (mean 24·5% increase in patients vs mean 65% increase in healthy controls, p<0·0001). Our results support the hypothesis that there is an association between P-glycoprotein overactivity in some regions of the brain and pharmacoresistance in temporal lobe epilepsy. If this relation is confirmed, and P-glycoprotein can be identified as a contributor to pharmacoresistance, overcoming P-glycoprotein overactivity could be investigated as a potential treatment strategy. EU-FP7 programme (EURIPIDES number 201380).
    The Lancet Neurology 06/2013; DOI:10.1016/S1474-4422(13)70109-1 · 21.82 Impact Factor
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    ABSTRACT: INTRODUCTION: The adenosine triphosphate-binding cassette (ABC) transporter P-glycoprotein (Pgp) protects the brain from accumulation of lipophilic compounds by active efflux transport across the blood-brain barrier. Changes in Pgp function/expression may occur in neurological disorders, such as epilepsy, Alzheimer's or Parkinson's disease. In this work we investigated the suitability of the radiolabeled Pgp inhibitors [(11)C]elacridar and [(11)C]tariquidar to visualize Pgp density in rat brain with PET. METHODS: Rats underwent a first PET scan with [(11)C]elacridar (n=5) or [(11)C]tariquidar (n=6) followed by a second scan with the Pgp substrate (R)-[(11)C]verapamil after administration of unlabeled tariquidar at a dose which half-maximally inhibits cerebral Pgp (3mg/kg). Compartmental modeling using an arterial input function and Logan graphical analysis were used to estimate rate constants and volumes of distribution (VT) of radiotracers in different brain regions. RESULTS: Brain PET signals of [(11)C]elacridar and [(11)C]tariquidar were very low (~0.5 standardized uptake value, SUV). There was a significant negative correlation between VT and K1 (i.e. influx rate constant from plasma into brain) values of [(11)C]elacridar or [(11)C]tariquidar and VT and K1 values of (R)-[(11)C]verapamil in different brain regions which was consistent with binding of [(11)C]inhibitors to Pgp and efflux of (R)-[(11)C]verapamil by Pgp. CONCLUSION: The small Pgp binding signals obtained with [(11)C]elacridar and [(11)C]tariquidar limit the applicability of these tracers to measure cerebral Pgp density. PET tracers with higher (i.e. subnanomolar) binding affinities will be needed to visualize the low density of Pgp in brain.
    Nuclear Medicine and Biology 06/2013; DOI:10.1016/j.nucmedbio.2013.05.005 · 2.41 Impact Factor
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    ABSTRACT: Efflux transporters located at the blood-brain barrier, such as P-gp and BCRP, regulate the passage of many drugs in and out of the brain. Changes in the function and density of these proteins, in particular P-gp, may play a role in several neurological disorders. Several radioligands have been developed for measuring P-gp function at the blood-brain barrier of human subjects with positron emission tomography (PET). However, attempts to measure P-gp density with radiolabeled inhibitors that bind to these proteins in vivo have not thus far provided useful, quantifiable PET signals. Herein, we argue that not only the low density of transporters in the brain as a whole but also their very high density in brain capillaries act to lower the concentration of ligand in the plasma and thereby contribute to absent or low signals in PET studies of P-gp density. Our calculations, based on published data and theoretical approximations, estimate that whole brain densities of many efflux transporters at the blood-brain barrier range from 0.04 to 5.19 nM. We conclude that the moderate affinities (> 5 nM) of currently labeled inhibitors may not allow measurement of efflux transporter density at the blood-brain barrier, and inhibitors with substantially higher affinity will be needed for density imaging of P-gp and other blood-brain barrier transporters.
    Molecular Pharmaceutics 04/2013; 10(6). DOI:10.1021/mp400011g · 4.79 Impact Factor
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    ABSTRACT: Brain penetration of radiopharmaceuticals or therapeutic drugs may be restricted by adenosine triphosphate-binding cassette (ABC) transporters, such as P-glycoprotein (Pgp), breast cancer resistance protein (BCRP), or the multidrug resistance-associated proteins. These transporters are expressed in the luminal membrane of brain capillary endothelial cells forming the blood-brain barrier (BBB), where they actively efflux a wide range of chemically unrelated compounds from the brain back into the blood. Most efforts to visualize ABC transporters at the BBB with positron emission tomography have concentrated on Pgp. Pgp imaging probes can be classified as radiolabeled substrates or inhibitors. The radiolabeled substrates (R)-[(11) C]verapamil and [(11) C]-N-desmethyl-loperamide have been successfully used to assess Pgp function at the BBB of animals and humans. Radiolabeled Pgp inhibitors, such as [(11) C]tariquidar, [(11) C]elacridar, or [(11) C]laniquidar, were developed to measure Pgp expression levels at the BBB, which has so far remained unsuccessful as these probes were unexpectedly recognized at tracer concentrations by Pgp and BCRP as substrates resulting in low brain uptake. Studies on positron emission tomography tracers for other ABC transporters than Pgp (BCRP and multidrug resistance-associated proteins) are still in their infancy. It is hoped that the experience gained with the imaging of Pgp will be successfully translated to the development of radiotracers to visualize other ABC transporters.Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Labelled Compounds 03/2013; 56(3-4):68-77. DOI:10.1002/jlcr.2993
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    ABSTRACT: Elacridar and tariquidar are generally thought to be non-transported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of elacridar and tariquidar by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labelled elacridar and tariquidar before and after MDT inhibition in wild-type and transporter knockout mice as well as in in-vitro transport assays in MDT-overexpressing cells. Brain entrance of [(11)C]elacridar and [(11)C]tariquidar administered in nanomolar tracer doses was found to be limited by Pgp- and Bcrp1-mediated efflux at the mouse blood-brain barrier. At higher, MDT-inhibitory doses, i.e. 15 mg/kg for tariquidar and 5 mg/kg for elacridar, brain activity uptake of [(11)C]elacridar at 25 min after tracer injection was 5.8±0.3, 2.1±0.2 and 7.5±1.0-fold higher in wild-type, Mdr1a/b((-/-,)) and Bcrp1((-/-)) mice, respectively, but remained unchanged in Mdr1a/b((-/-)) Bcrp1((-/-)) mice. Activity uptake of [(11)C]tariquidar was 2.8±0.2 and 6.8±0.4-fold higher in wild-type and Bcrp1((-/-)) mice, but remained unchanged in Mdr1a/b((-/-)) and Mdr1a/b((-/-)) Bcrp1((-/-)) mice. Consistent with the in-vivo findings, in-vitro uptake assays in Pgp and Bcrp1 overexpressing cell lines confirmed low intracellular accumulation of elacridar and tariquidar at nanomolar concentrations and increased uptake at micromolar concentrations. As this study shows that microdoses can behave pharmacokinetically different from MDT-inhibitory doses if a compound interacts with MDTs, conclusions from microdose studies should be drawn carefully.
    Drug metabolism and disposition: the biological fate of chemicals 01/2013; 41(4). DOI:10.1124/dmd.112.049148 · 3.33 Impact Factor
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    ABSTRACT: We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after intravenous administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable of inhibiting Pgp at the blood-brain barrier. Fifteen male healthy volunteers were randomized to receive single intravenous doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling for over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography mass spectrometry. No dose-limiting toxicities of TQD were observed. The area under the plasma concentration-time curve from start until 24 h after the end of infusion was positively correlated with an administered TQD dose (r = 0.8981, p < 0.0001). Moreover, we found a positive correlation for volume of distribution at steady state (r = 0.7129, p = 0.0004) with TQD dose. Dose dependency of volume of distribution at steady state points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability as well as dose-linear increases in plasma exposure support the future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human blood-brain barrier.
    Pharmacology 11/2012; 91(1-2):12-19. DOI:10.1159/000343243 · 1.58 Impact Factor
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    ABSTRACT: Background This study investigated the influence of P-glycoprotein (P-gp) inhibitor tariquidar on the pharmacokinetics of P-gp substrate radiotracer (R)-[11C]verapamil in plasma and brain of rats and humans by means of positron emission tomography (PET). Methods Data obtained from a preclinical and clinical study, in which paired (R)-[11C]verapamil PET scans were performed before, during, and after tariquidar administration, were analyzed using nonlinear mixed effects (NLME) modeling. Administration of tariquidar was included as a covariate on the influx and efflux parameters (Qin and Qout) in order to investigate if tariquidar increased influx or decreased outflux of radiotracer across the blood–brain barrier (BBB). Additionally, the influence of pilocarpine-induced status epilepticus (SE) was tested on all model parameters, and the brain-to-plasma partition coefficient (VT-NLME) was calculated. Results Our model indicated that tariquidar enhances brain uptake of (R)-[11C]verapamil by decreasing Qout. The reduction in Qout in rats during and immediately after tariquidar administration (sevenfold) was more pronounced than in the second PET scan acquired 2 h after tariquidar administration (fivefold). The effect of tariquidar on Qout in humans was apparent during and immediately after tariquidar administration (twofold reduction in Qout) but was negligible in the second PET scan. SE was found to influence the pharmacological volume of distribution of the central brain compartment Vbr1. Tariquidar treatment lead to an increase in VT-NLME, and pilocarpine-induced SE lead to increased (R)-[11C]verapamil distribution to the peripheral brain compartment. Conclusions Using NLME modeling, we were able to provide mechanistic insight into the effects of tariquidar and SE on (R)-[11C]verapamil transport across the BBB in control and 48 h post SE rats as well as in humans.
    10/2012; 2(1):58. DOI:10.1186/2191-219X-2-58

Publication Stats

1k Citations
306.49 Total Impact Points


  • 2009–2015
    • AIT Austrian Institute of Technology
      • Department of Health & Environment
      Wien, Vienna, Austria
  • 2003–2013
    • Medical University of Vienna
      • Department of Clinical Pharmacology
      Wien, Vienna, Austria
  • 2011
    • VU University Medical Center
      • Department of Neurology
      Amsterdamo, North Holland, Netherlands
  • 2010
    • University of Turku
      Turku, Province of Western Finland, Finland
    • University of Veterinary Medicine Hannover
      • Institute of Pathology
      Hanover, Lower Saxony, Germany
  • 2004–2010
    • University of Vienna
      • Department of Medicinal Chemistry
      Vienna, Vienna, Austria
    • Karolinska Institutet
      • Institutionen för klinisk neurovetenskap
      Stockholm, Stockholm, Sweden
  • 1999–2004
    • Karolinska University Hospital
      Tukholma, Stockholm, Sweden
  • 2001
    • Cea Leti
      Grenoble, Rhône-Alpes, France
  • 2000
    • Atomic Energy and Alternative Energies Commission
      Fontenay, Île-de-France, France