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The AAPS Journal

, 20:16 | Cite as

Demonstration of Nucleoside Transporter Activity in the Nose-to-Brain Distribution of [18F]Fluorothymidine Using PET Imaging

  • Laura L. Boles Ponto
  • Jiangeng Huang
  • Susan A. Walsh
  • Michael R. Acevedo
  • Christine Mundt
  • John Sunderland
  • Maureen Donovan
Research Article Theme: Advances and Applications of In Vivo Medical Imaging in Drug Development and Regulation
Part of the following topical collections:
  1. Theme: Advances and Applications of In Vivo Medical Imaging in Drug Development and Regulation

Abstract

To evaluate the role of nucleoside transporters in the nose-to-brain uptake of [18F]fluorothymidine (FLT), an equilibrative nucleoside transporter (ENT1,2) and concentrative nucleoside transporter (CNT1–3) substrate, using PET to measure local tissue concentrations. Anesthetized Sprague-Dawley rats were administered FLT by intranasal (IN) instillation or tail-vein injection (IV). NBMPR (nitrobenzylmercaptopurine riboside), an ENT1 inhibitor, was administered either IN or intraperitoneally (IP). Dynamic PET imaging was performed for up to 40 min. A CT was obtained for anatomical co-registration and attenuation correction. Time-activity curves (TACs) were generated for the olfactory bulb (OB) and remaining brain, and the area-under-the-curve (AUC) for each TAC was calculated to determine the total tissue exposure of FLT. FLT concentrations were higher in the OB than in the rest of the brain following IN administration. IP administration of NBMPR resulted in increased OB and brain FLT exposure following both IN and IV administration, suggesting that NBMPR decreases the clearance rate of FLT from the brain. When FLT and NBMPR were co-administered IN, there was a decrease in the OB AUC while an increase in the brain AUC was observed. The decrease in OB exposure was likely the result of inhibition of ENT1 uptake activity in the nose-to-brain transport pathway. FLT distribution patterns show that nucleoside transporters, including ENT1, play a key role in the distribution of transporter substrates between the nasal cavity and the brain via the OB.

KEY WORDS

Intranasal administration Nucleoside transporters [18F]fluorothymidine ENT1 CNT3 Nose-to-brain transport 

Notes

Acknowledgments

Research reported in this publication was supported by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health under award number R01DC008374-03S1. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Laura L. Boles Ponto
    • 1
    • 2
  • Jiangeng Huang
    • 3
    • 4
  • Susan A. Walsh
    • 1
  • Michael R. Acevedo
    • 1
  • Christine Mundt
    • 1
    • 2
  • John Sunderland
    • 1
    • 2
  • Maureen Donovan
    • 3
  1. 1.Roy J. and Lucille A. Carver College of Medicine, Department of RadiologyUniversity of IowaIowa CityUSA
  2. 2.PET Imaging CenterUniversity of Iowa Hospitals and ClinicsIowa CityUSA
  3. 3.College of Pharmacy, Division of Pharmaceutics and Translational TherapeuticsUniversity of IowaIowa CityUSA
  4. 4.Department of Pharmaceutics, School of Pharmacy, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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