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Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2

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Abstract

Rationale

Central norepinephrine transporter (NET) is one of the main targets of antidepressants. Although the measurement of NET occupancy has been attempted in humans, the outcomes have been inconclusive.

Objective

In this study, the occupancy of NET by different doses of an antidepressant, nortriptyline, was measured using positron emission tomography (PET) with (S,S)-[18F]FMeNER-D2.

Materials and methods

PET scans using (S,S)-[18F]FMeNER-D2 were performed on six healthy men before and after oral administration of a single oral dose of nortriptyline (10–75 mg). After a bolus i.v. injection of (S,S)-[18F]FMeNER-D2, dynamic scanning was performed for 0–90 min, followed by scanning for 120–180 min. The ratio of the thalamus-to-caudate areas under the curve (120–180 min) minus 1 was used as the binding potential (BPND) for NET. NET occupancy was calculated as the percentage reduction of BPND. Venous blood samples were taken to measure the concentrations of nortriptyline just before injection of the tracer and at 180 min after the injection.

Results

Mean NET occupancies by nortriptyline were 16.4% at 10 mg, 33.2% at 25 mg, and 41.1% at 75 mg. The mean plasma concentration of nortriptyline was less than the lower limit of detection at 10 mg, 23.7 ng/mL at 25 mg, and 50.5 ng/mL at 75 mg. Estimated ED50 was 76.8 mg of administration dose and 59.8 ng/mL of plasma concentration.

Conclusions

NET occupancy by nortriptyline corresponding to the administration dose of 10–75 mg or plasma concentration was observed from 16% to 41%.

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Acknowledgement

This study was supported by a consignment expense for the Molecular Imaging Program on “Research Base for PET Diagnosis” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government, and a Health and Labor Sciences Research Grant for “Research on Psychiatric and Neurological Diseases and Mental Health” from the Ministry of Health, Labor, and Welfare, Japanese Government. All authors have no conflict of interest. We thank Dr. Fumitoshi Kodaka, Dr. Saori Fujie, Mr. Katsuyuki Tanimoto, Mr. Takahiro Shiraishi, and Mr. Toshio Miyamoto for their assistance in performing the PET experiments, and Ms. Yoshiko Fukushima for her help as clinical research coordinator at the National Institute of Radiological Sciences.

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Authors and Affiliations

  1. Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1, Anagawa, Inage-ku, Chiba, 263-8555, Japan

    Mizuho Sekine, Ryosuke Arakawa, Hiroshi Ito, Masaki Okumura, Takeshi Sasaki, Hidehiko Takahashi, Harumasa Takano & Tetsuya Suhara

  2. Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan

    Mizuho Sekine, Ryosuke Arakawa, Masaki Okumura & Yoshiro Okubo

  3. Department of Clinical Neuroscience, Psychiatry Section, Karolinska Institutet, Karolinska Hospital, Stockholm, Sweden

    Christer Halldin

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  1. Mizuho Sekine
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  2. Ryosuke Arakawa
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  3. Hiroshi Ito
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  4. Masaki Okumura
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  10. Tetsuya Suhara
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Correspondence to Hiroshi Ito.

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Sekine, M., Arakawa, R., Ito, H. et al. Norepinephrine transporter occupancy by antidepressant in human brain using positron emission tomography with (S,S)-[18F]FMeNER-D2 . Psychopharmacology 210, 331–336 (2010). https://doi.org/10.1007/s00213-010-1824-9

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  • DOI: https://doi.org/10.1007/s00213-010-1824-9

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