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EJNMMI Research
Published in: EJNMMI Research 1/2014

Open Access 01-12-2014 | Original research

ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [11C]AZ10419369: a comparative PET study in mouse, rat, and guinea pig

Authors: Miklós Tóth, Jenny Häggkvist, Andrea Varrone, Sjoerd J Finnema, Janine Doorduin, Masaki Tokunaga, Makoto Higuchi, Balázs Gulyás, Christer Halldin

Published in: EJNMMI Research | Issue 1/2014

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Abstract

Background

We have explored the possibility that the serotonin 1B receptor radioligand [11C]AZ10419369 is a substrate for adenosine triphosphate (ATP)-binding cassette (ABC) transporters, such as P-glycoprotein (P-gp), Mrp4, and Bcrp, in rodents and whether there is a species difference regarding its blood-brain barrier (BBB) penetration.

Methods

In a series of preclinical positron emission tomography measurements, we have administered [11C]AZ10419369 to mice, rats, and guinea pigs under baseline conditions and, on separate experimental days, after administration of the ABC transporter inhibitor, cyclosporin A (CsA).

Results

During baseline conditions, the brain uptake was low in mice and rats, but not in guinea pigs. After CsA pretreatment, the peak whole brain uptake values of [11C]AZ10419369 increased by 207% in mice, 94% in rats, and 157% in guinea pigs. Binding potentials (BPND) could not be estimated during baseline conditions in mice and rats. After CsA pretreatment, the highest BPND values were obtained in the striatum and thalamus (BPND ≈ 0.4) in mice, while in rats, the highest binding areas were the striatum, thalamus, hypothalamus, and periaqueductal gray (BPND ≈ 0.5). In guinea pigs, we did not find any significant changes in BPND between baseline and CsA pretreatment, except in the striatum.

Conclusions

The results indicate that BBB penetration of [11C]AZ10419369 was hindered by ABC transporter activity in mouse, rat, and guinea pig. This study highlights the importance of ABC transporters in the design of preclinical positron emission tomography (PET) studies.
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Metadata
Title
ABC transporter-dependent brain uptake of the 5-HT1B receptor radioligand [11C]AZ10419369: a comparative PET study in mouse, rat, and guinea pig
Authors
Miklós Tóth
Jenny Häggkvist
Andrea Varrone
Sjoerd J Finnema
Janine Doorduin
Masaki Tokunaga
Makoto Higuchi
Balázs Gulyás
Christer Halldin
Publication date
01-12-2014
Publisher
Springer Berlin Heidelberg
Published in
EJNMMI Research / Issue 1/2014
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-014-0064-0

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