Linked Life Data

21419632

Source:http://linkedlifedata.com/resource/pubmed/id/21419632

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
7
pubmed:dateCreated
2011-3-29
pubmed:abstractText
Aim of this study was to label the potent dual P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) inhibitor elacridar (1) with (18)F to provide a positron emission tomography (PET) radiotracer to visualize Pgp and BCRP. A series of new 1- and 2-halogen- and nitro-substituted derivatives of 1 (4a-e) was synthesized as precursor molecules and reference compounds for radiolabelling and shown to display comparable in vitro potency to 1 in increasing rhodamine 123 accumulation in a cell line overexpressing human Pgp (MDCKII-MDR1). 1-[(18)F]fluoroelacridar ([(18)F]4b) was synthesized in a decay-corrected radiochemical yield of 1.7±0.9% by a 1-step no-carrier added nucleophilic aromatic (18)F-substitution of 1-nitro precursor 4c. Small-animal PET imaging of [(18)F]4b was performed in naïve rats, before and after administration of unlabelled 1 (5 mg/kg, n=3), as well as in wild-type and Mdr1a/b((-/-))Bcrp1((-/-)) mice (n=3). In PET experiments in rats, administration of unlabelled 1 increased brain activity uptake by a factor of 9.5 (p=0.0002, 2-tailed Student's t-test), whereas blood activity levels remained unchanged. In Mdr1a/b((-/-))Bcrp1((-/-)) mice, the mean brain-to-blood ratio of activity at 60 min after tracer injection was 7.6 times higher as compared to wild-type animals (p=0.0002). HPLC analysis of rat brain tissue extracts collected at 40 min after injection of [(18)F]4b revealed that 93±7% of total radioactivity in brain was in the form of unchanged [(18)F]4b. In conclusion, the in vivo behavior of [(18)F]4b was found to be similar to previously described [(11)C]1 suggesting transport of [(18)F]4b by Pgp and/or BCRP at the rodent BBB. However, low radiochemical yields and a significant degree of in vivo defluorination will limit the utility of [(18)F]4b as a PET tracer.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
1464-3391
pubmed:author
pubmed:copyrightInfo
Copyright © 2011 Elsevier Ltd. All rights reserved.
pubmed:issnType
Electronic
pubmed:day
1
pubmed:volume
19
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2190-8
pubmed:meshHeading
pubmed-meshheading:21419632-ATP-Binding Cassette Transporters, pubmed-meshheading:21419632-Acridines, pubmed-meshheading:21419632-Animals, pubmed-meshheading:21419632-Blood-Brain Barrier, pubmed-meshheading:21419632-Breast Neoplasms, pubmed-meshheading:21419632-Drug Resistance, Multiple, pubmed-meshheading:21419632-Female, pubmed-meshheading:21419632-Fluorine Radioisotopes, pubmed-meshheading:21419632-Humans, pubmed-meshheading:21419632-Isotope Labeling, pubmed-meshheading:21419632-Mice, pubmed-meshheading:21419632-Models, Molecular, pubmed-meshheading:21419632-Neoplasm Proteins, pubmed-meshheading:21419632-P-Glycoprotein, pubmed-meshheading:21419632-Positron-Emission Tomography, pubmed-meshheading:21419632-Radiopharmaceuticals, pubmed-meshheading:21419632-Rats, pubmed-meshheading:21419632-Rats, Sprague-Dawley, pubmed-meshheading:21419632-Tetrahydroisoquinolines, pubmed-meshheading:21419632-Tissue Distribution
pubmed:year
2011
pubmed:articleTitle
Radiosynthesis and in vivo evaluation of 1-[18F]fluoroelacridar as a positron emission tomography tracer for P-glycoprotein and breast cancer resistance protein.
pubmed:affiliation
Department of Medicinal Chemistry, University of Vienna, Austria.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't