Synthesis and In Vivo Imaging of N-(3-[11C]Methoxybenzyl)-2-(3-Methoxyphenyl)ethylaniline as a Potential Targeting Agent for P-glycoprotein
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The plasma membrane P-glycoprotein (Pgp) is an efflux transporter involved in multidrug resistance and in the onset of neurodegenerative disease. Its function and most mechanisms of action are still under investigation. We developed a C-11-labeled 2-arylethylphenylamine-([11C]AEPH) derivative for positron emission tomography (PET), as a novel probe to better understand the activity and the function of Pgp in vivo.
The synthetic procedure and the quality control of the selected lead compound, [11C]AEPH-1, were set up and optimized. The biodistribution and the dynamic extraction in target organs of [11C]AEPH-1 were studied in vivo by PET in healthy rats at baseline and after pre-treatment with a Pgp inhibitor (tariquidar).
In vivo dynamic imaging was consistent with the results of ex vivo extraction on explanted organs. An adequate stability for in vivo studies, as well as a high activity of [11C]AEPH-1 in intestine and barrier tissues, has been demonstrated. Results of the blockade study showed a decrease of uptake after the pre-treatment, indicating a behavior attributable to a Pgp ligand.
The suitable pharmacokinetics and the specificity tested in the pre-treated animals have indicated the potentiality of this AEPH derivative to act as Pgp ligand, providing new opportunities for further studies on expression and function of this important efflux transporter in the fields of neurology and oncology.
Key wordsP-glycoprotein Multidrug resistance CNS radiotracers [11C]-Methylation Arylethylphenylamine derivatives Arylethylphenoxy derivatives Pgp inhibitor Tariquidar
This study was partially supported by the grant PRIN2009 (20097FJHPZ_003) from the Ministero dell’Istruzione dell’Università e della Ricerca (MIUR) Italy.
Compliance with Ethical Standards
The experimental protocol, which conformed to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85–23, revised 1996), was approved by the Animal Care Committee of the Italian Ministry of Health (protocol no. 0000249/2014).
Conflict of Interest
The authors declare that they have no conflict of interest.
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