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Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration

  • Research Article
  • Theme: Advances and Applications of In Vivo Medical Imaging in Drug Development and Regulation
  • Published:
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Abstract

To illustrate the use of imaging to quantify the transfer of materials from the nasal cavity to other anatomical compartments, specifically, transfer to the brain using the thymidine analogue, [18F]fluorothymidine (FLT), and the glucose analogue, [18F]fluorodeoxyglucose (FDG). Anesthetized rats were administered FLT or FDG by intranasal instillation (IN) or tail-vein injection (IV). PET/CT imaging was performed for up to 60 min. Volumes-of-interest (VOIs) for the olfactory bulb (OB) and the remaining brain were created on the CT and transferred to the co-registered dynamic PET. Time-activity curves (TACs) were generated and compared. The disposition patterns were successfully visualized and quantified and differences in brain distribution patterns were observed. For FDG, the concentration was substantially higher in the OB than the brain only after IN administration. For FLT, the concentration was higher in the OB than the brain after both IN and IV and higher after IN than after IV administration at all times, whereas the concentration in the brain was higher after IN than after IV administration at early times only. Approximately 50 and 9% of the IN FDG and FLT doses, respectively, remained in the nasal cavity at 20 min post-administration. The initial phase of clearance was similar for both agents (t1/2 = 2.53 and 3.36 min) but the slow clearance phase was more rapid for FLT than FDG (t1/2 = 32.1 and 85.2 min, respectively). Pharmacoimaging techniques employing PET/CT can be successfully implemented to quantitatively investigate and compare the disposition of radiolabeled agents administered by a variety of routes.

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Notes

  1. The University of Iowa’s IND for FLT is essentially equivalent to that utilized in the FLT Demonstration Project of the Clinical Trials Network of the Society of Nuclear Medicine and Molecular Imaging (SNMMI CTN). For further information on specifications for FLT, see the Centralized Biomarker INDs, http://www.snm.org/index.cfm?PageID=8819.

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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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Authors and Affiliations

  1. Department of Radiology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA

    Laura L. Boles Ponto, Susan Walsh, Christine Mundt, Katherine Thede-Reynolds, G. Leonard Watkins, John Sunderland & Michael Acevedo

  2. PET Imaging Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, Iowa, 52242, USA

    Laura L. Boles Ponto, Christine Mundt, Katherine Thede-Reynolds, G. Leonard Watkins & John Sunderland

  3. College of Pharmacy, Division of Pharmaceutics and Translational Therapeutics, Iowa City, Iowa, USA

    Jiangeng Huang & Maureen Donovan

  4. Department of Pharmaceutics, School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Jiangeng Huang

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  1. Laura L. Boles Ponto
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Correspondence to Laura L. Boles Ponto.

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Guest Editors: Peng Zou, Doanh Tran, and Edward Bashaw

Electronic supplementary material

Figure S1

Cine of 3-dimensional reconstruction of dynamic PET data after [18F]FLT intranasal administration co-registered with CT, thresholded to display skeleton of rat. The rainbow colors reflect the concentration of FLT (red>yellow>blue). Note the migration and swallowing of dose. The intensity of the signal from the dose volume visually swamps the signal of FLT in the olfactory bulb and rest of the brain. (MP4 288 kb)

Figure S2

Cine of 3-dimensional reconstruction of dynamic PET data after [18F]FLT intranasal administration co-registered with CT, thresholded to display outer contours of the rat. The rainbow colors reflect the concentration of FLT (red>yellow>blue). Note the presence of the dose in a single nostril only and the subsequent migration and swallowing of dose. (MP4 971 kb)

Preparation of [18F]Fluorothymidine (FLT) for Small Animal and Cell Culture Studies

Preparation of [18F]Fluorothymidine (FLT) for Small Animal and Cell Culture Studies

Final sterile [18F]Fluorothymidine (FLT) product, prepared according to IND # 101023 (Dr. Michael Graham, MD, PhD, PI) typically contains 80–120 mCi in 14–17 mL with approximately 9% ethanol content. This product is modified to meet the requirements for administration to small animals. A 1.5–2.0 mL sample is withdrawn from the product vial into a clean 13 mm × 100 mm borosilicate tube. The tube is then transferred to a stirred oil bath that has been pre-equilibrated to 90–95°C. The sample is heated under a steady stream of dry nitrogen for 12 min. A 3 1/2 in sterile arterial needle is used to direct the stream of nitrogen close to the surface of the FLT solution. At approximately 10 min, the needle is gradually withdrawn in order to blow off ethanol that may have condensed on the wall of the tube. Water condensate is always observed during this processing. The tube is withdrawn from the oil bath, rapidly wiped free of oil, and the top covered with Parafilm™ to avoid ingress of microbial agents. This material, when cooled, is apportioned to sterile plastic microfuge tubes as requested by the imaging facility using sterile pipet tips. Samples are removed for the analysis of ethanol content by gas chromatography and for final product quality control in a manner identical to the original human product using HPLC.

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Ponto, L.L.B., Walsh, S., Huang, J. et al. Pharmacoimaging of Blood-Brain Barrier Permeable (FDG) and Impermeable (FLT) Substrates After Intranasal (IN) Administration. AAPS J 20, 15 (2018). https://doi.org/10.1208/s12248-017-0157-6

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