Kooperativer Bibliotheksverbund

In: Journal of Labelled Compounds and Radiopharmaceuticals, March 2013, Vol.56(3-4), pp.68-77

Description: 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 ()‐[C]verapamil and [C]‐‐desmethyl‐loperamide have been successfully used to assess Pgp function at the BBB of animals and humans. Radiolabeled Pgp inhibitors, such as [C]tariquidar, [C]elacridar, or [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. Positron emission tomography radiotracers to visualize the efflux transporter P‐glycoprotein at the blood–brain barrier have been classified as radiolabeled substrates, such as ()‐[C]verapamil and [C]‐‐desmethyl‐loperamide, or radiolabeled inhibitors, such as [C]tariquidar or [C]elacridar. For other efflux transporters than P‐glycoprotein, such as breast cancer resistance protein or the multidrug resistance‐associated proteins, only very few positron emission tomography tracers are currently available.

Keywords: Positron Emission Tomography ; Adenosine‐Triphosphate Binding Cassette Abc Transporter ; Blood–Brain Barrier ; P‐Glycoprotein ; Breast Cancer Resistance Protein ; Multidrug Resistance‐Associated Proteins ; C ; F ; ‐[C]Verapamil ; [C]‐‐Desmethyl‐Loperamide

ISSN: 0362-4803

E-ISSN: 1099-1344

DOI: 10.1002/jlcr.2993

Language: English

In: Nuclear Medicine and Biology, 2015, Vol.42(7), p.585(5)

Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.nucmedbio.2015.03.004 Byline: Thomas Wanek, Alexander Traxl, Jens P. Bankstahl, Marion Bankstahl, Michael Sauberer, Oliver Langer, Claudia Kuntner Abstract: Transport of 2-[.sup.18F]fluoro-2-deoxy-d-glucose ([.sup.18F]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 [.sup.18F]FDG brain PET data. Aim of this study was to assess the influence of ABCB1 and ABCG2 at the BBB on brain distribution of [.sup.18F]FDG in vivo by performing [.sup.18F]FDG PET scans in wild-type and transporter knockout mice and by evaluating changes in [.sup.18F]FDG brain distribution after transporter inhibition. Article History: Received 29 October 2014; Revised 9 February 2015; Accepted 11 March 2015 Article Note: (footnote) [star] This is a free access article and can also be viewed on the journal's Web site (www.nucmedio.com). Complimentary access to this article is available until the next issue publishes online.

Keywords: Breast Cancer ; Glucose ; Brain

ISSN: 0969-8051

Source: Cengage Learning, Inc.

Language: English

In: Bioorganic & Medicinal Chemistry, 01 November 2016, Vol.24(21), pp.5326-5339

Description: Positron emission tomography (PET) using fluorine-18 ( F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6′-deoxy-6′-[ F]fluoro-β- -allofuranosyl)-2-nitroimidazole (β-[ F] ), a putative nucleoside transporter substrate, was synthetized by nucleophilic [ F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (β- ) in a final radiochemical yield of 12 ± 8% ( = 10, based on [ F]fluoride starting activity) in a total synthesis time of 60 min with a specific activity at end of synthesis of 218 ± 58 GBq/μmol ( = 10). Both radiolabeling precursor β- and unlabeled reference compound β- were prepared in multistep syntheses starting from 1,2:5,6-di- -isopropylidene-α- -allofuranose. In vitro experiments demonstrated an interaction of β- with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of β-[ F] in tumor cell lines. In biodistribution studies in healthy mice β-[ F] showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13 ± 0.22 ( = 4) at 2 h after administration of β-[ F] . In ex vivo autoradiography experiments β-[ F] distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, β-[ F] shows potential as PET hypoxia radiotracer which merits further investigation.

Keywords: Β-6′-[18f]Fazal ; Pimonidazole ; Pet ; Azomycin Nucleosides ; Medicine ; Chemistry ; Anatomy & Physiology

ISSN: 0968-0896

E-ISSN: 1464-3391

DOI: 10.1016/j.bmc.2016.08.053

URL: View record in ScienceDirect (Access to full text may be restricted)

Language: English

In: Angewandte Chemie International Edition, 09/01/2014, Vol.53(36), pp.9675-9675

Description: Bioorthogonal PET probes serve as highly valuable tools in the field of pretargeted molecular imaging. In their Communication on page 9655 ff., H. Mikula, C. Kuntner, and co‐workers describe the development, synthesis, and characterization of a low‐molecular‐weight 18 F‐labeled tetrazine derivative that can be used for bioorthogonal PET imaging of dienophile‐tagged (bio)molecules through the application of in vivo chemistry.

Keywords: Chemistry;

ISSN: Angewandte Chemie International Edition

E-ISSN: 14337851

E-ISSN: 15213773

DOI: 10.1002/anie.201406154

Source: Wiley (via CrossRef)

Language: English

In: Angewandte Chemie International Edition, 01 September 2014, Vol.53(36), pp.9655-9659

Description: A low‐molecular‐weight F‐labeled tetrazine derivative was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of F through additional steps were evaded by direct F‐fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddition with trans‐cyclooctenes were investigated by applying quantum chemical calculations and stopped‐flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile‐tagged (bio)molecules. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the F‐labeled tetrazine that also passes the blood–brain barrier. An in vivo click experiment confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chemical and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research. A low‐molecular‐weight radiolabeled tetrazine derivative was prepared by direct [F]‐fluorination (see structure on the left in the figure). PET/MR imaging revealed fast and homogenous biodistribution including in the brain (right). PET/MR=positron emission tomography/magnetic resonance.

Keywords: Bioorthogonal Chemistry ; Click Chemistry ; Imaging Agents ; Kinetics ; Tetrazines

ISSN: 1433-7851

E-ISSN: 1521-3773

DOI: 10.1002/anie.201404277

Language: English

In: European Journal of Nuclear Medicine and Molecular Imaging, 2012, Vol.39(1), pp.149-159

Description: Byline: Thomas Wanek (1), Claudia Kuntner (1), Jens P. Bankstahl (2), Marion Bankstahl (2), Johann Stanek (1,3), Michael Sauberer (1), Severin Mairinger (1,3,4), Sabine Strommer (3), Volker Wacheck (3), Wolfgang Loscher (2), Thomas Erker (4), Markus Muller (3), Oliver Langer (1,3) Keywords: Multidrug resistance; P-glycoprotein; Positron emission tomography; [[.sup.11]C]Tariquidar; [[.sup.11]C]Elacridar; (R)[-[.sup.11]C]Verapamil Abstract: Purpose One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [[.sup.11]C]tariquidar and [[.sup.11]C]elacridar with the Pgp substrate radiotracer (R)[-[.sup.11]C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. Methods Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [[.sup.11]C]tariquidar (n=7), [[.sup.11]C]elacridar (n=6) and (R)[-[.sup.11]C]verapamil (n=7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. Results [11C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean+-SD areas under the time--activity curves in scan 1 from time 0 to 60 min (AUC.sub.0--60) were 38.8+-2.2 min and 25.0+-5.3 min (p=0.016, Wilcoxon matched pairs test). [[.sup.11]C]Elacridar and (R)[-[.sup.11]C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [[.sup.11]C]tariquidar, [[.sup.11]C]elacridar and (R)[-[.sup.11]C]verapamil. Conclusion Among the tested radiotracers, [[.sup.11]C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [[.sup.11]C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours. Author Affiliation: (1) Health & Environment Department, Molecular Medicine, AIT Austrian Institute of Technology GmbH, 2444, Seibersdorf, Austria (2) Department of Pharmacology, Toxicology & Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany (3) Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria (4) Department of Medicinal Chemistry, University of Vienna, Vienna, Austria Article History: Registration Date: 09/09/2011 Received Date: 24/05/2011 Accepted Date: 09/09/2011 Online Date: 08/10/2011 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00259-011-1941-7) contains supplementary material, which is available to authorized users.

Keywords: Multidrug resistance ; P-glycoprotein ; Positron emission tomography ; [C]Tariquidar ; [C]Elacridar ; ()-[C]Verapamil

ISSN: 1619-7070

E-ISSN: 1619-7089

DOI: 10.1007/s00259-011-1941-7

URL: View full text in Springer (Subscribers only)

Language: English

In: European Journal of Pharmacology, 05 December 2012, Vol.696(1-3), pp.18-27

Description: HM30181, a potent and selective inhibitor of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp), was shown to enhance oral bioavailability and improve antitumour efficacy of paclitaxel in mouse tumour models. In search for a positron emission tomography (PET) radiotracer to visualise Pgp expression levels at the blood–brain barrier (BBB), we examined the ability of HM30181 to inhibit Pgp at the murine BBB. HM30181 was shown to be approximately equipotent with the reference Pgp inhibitor tariquidar in inhibiting rhodamine 123 efflux from CCRF-CEM T cells (IC , tariquidar: 8.2±2.0 nM, HM30181: 13.1±2.3 nM). PET scans with the Pgp substrate ( )-[ C]verapamil in FVB wild-type mice pretreated i.v. with HM30181 (10 or 21 mg/kg) failed to show significant increases in ( )-[ C]verapamil brain uptake compared with vehicle treated animals. PET scans with [ C]HM30181 showed low and not significantly different brain uptake of [ C]HM30181 in wild-type, and mice and significantly, 4.7-fold ( 〈0.01), higher brain uptake, relative to wild-type animals, in mice. This was consistent with HM30181 being at microdoses a dual substrate of Pgp and breast cancer resistance protein (Bcrp). autoradiography on low (EMT6) and high (EMT6Ar1.0) Pgp expressing murine breast tumour sections showed 1.9 times higher binding of [ C]HM30181 in EMT6Ar1.0 tumours ( 〈0.001) which was displaceable with unlabelled tariquidar, elacridar or HM30181 (1 μM). Our data suggest that HM30181 is not able to inhibit Pgp at the murine BBB at clinically feasible doses and that [ C]HM30181 is not suitable as a PET tracer to visualise cerebral Pgp expression levels.

Keywords: P-Glycoprotein ; Blood–Brain Barrier ; Hm30181 ; Tariquidar ; Positron Emission Tomography ; Microdosing ; Pharmacy, Therapeutics, & Pharmacology

ISSN: 0014-2999

E-ISSN: 1879-0712

DOI: 10.1016/j.ejphar.2012.09.013

URL: View record in ScienceDirect (Access to full text may be restricted)

Language: English

In: Journal of Pharmaceutical Sciences, January 2016, Vol.105(1), pp.106-112

Description: 24- -ursodeoxycholic acid ( UDCA) is a novel therapeutic approach to cholestatic liver diseases. In mouse models of cholestasis, UDCA induces basolateral multidrug resistance–associated proteins 4 (Mrp4) and 3 in hepatocytes, which provide alternative escape routes for bile acids accumulating during cholestasis but could also result in altered hepatic disposition of concomitantly administered substrate drugs. We used positron emission tomography imaging to study the influence of UDCA on hepatic disposition of the model Mrp4 substrate [ F]ciprofloxacin in wild-type and mice, a model of cholestasis. Animals underwent [ F]ciprofloxacin positron emission tomography at baseline and after UDCA treatment. After UDCA treatment, liver-to-blood area under the curve ratio of [ F]ciprofloxacin was significantly decreased compared to baseline, both in wild-type (−34.0 ± 2.1%) and mice (−20.5 ± 6.0%). [ F]Ciprofloxacin uptake clearance from blood into liver was reduced by −17.1 ± 9.0% in wild-type and by −20.1 ± 7.3% in mice. Real-time PCR analysis showed significant increases in hepatic Mrp4 and multidrug resistance–associated protein 3 mRNA after UDCA. Transport experiments in organic anion transporting polypeptide (OATP)1B1-, OATP1B3-, and OATP2B1-transfected cells revealed weak transport of [ C]ciprofloxacin by OATP1B3 and OATP2B1 and no inhibition by UDCA. In conclusion, our data suggest that changes in hepatic [ F]ciprofloxacin disposition in mice after UDCA treatment were caused by induction of basolateral Mrp4 in hepatocytes.

Keywords: Pet ; Drug Interactions ; Hepatic Transport ; ABC Transporters ; Multidrug Resistance–Associated Proteins ; Organic Anion-Transporting Polypeptide Transporters ; Hepatobiliary Disposition ; Pharmacy, Therapeutics, & Pharmacology

ISSN: 0022-3549

E-ISSN: 1520-6017

DOI: 10.1016/j.xphs.2015.11.014

URL: View record in ScienceDirect (Access to full text may be restricted)

Language: English

In: Cancer Research, 04/15/2010, Vol.70(8 Supplement), pp.4470-4470

ISSN: 0008-5472

E-ISSN: 1538-7445

DOI: 10.1158/1538-7445.AM10-4470

Source: CrossRef

Language: English

In: Angewandte Chemie International Edition, Sept 1, 2014, Vol.53(36), p.9655(5)

Keywords: Positron Emission Tomography ; Prostheses And Implants ; Chemical Kinetics

ISSN: 1433-7851

Source: Cengage Learning, Inc.