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11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

11C-labelled 1-[(S)-1-(2,3-dihydrobenzo[1,2]dioxin-2-yl)methyl]-4-(3-methoxy-methylpyridin-2-yl)-piperazine (11C-ORM-13070) is a novel PET tracer for imaging of α2C-adrenoceptors in the human brain. Brain α2C-adrenoceptors may be therapeutic targets in several neuropsychiatric disorders, including depression, schizophrenia and Alzheimer’s disease. To validate the use of 11C-ORM-13070 in humans, we investigated its radiometabolism, pharmacokinetics, whole-body distribution and radiation dose.

Methods

Radiometabolism was studied in a test–retest setting in six healthy men. After intravenous injection of 11C-ORM-13070, blood samples were drawn over 60 min. Plasma samples were analysed by radio-HPLC for intact tracer and its radioactive metabolites. Metabolite-corrected plasma time–activity curves were used for calculation of pharmacokinetics. In a separate group of 12 healthy men, the whole-body distribution of 11C-ORM-13070 and radiation exposure were investigated by dynamic PET/CT imaging without blood sampling.

Results

Two radioactive metabolites of 11C-ORM-13070 were detected in human arterial plasma. The proportion of unchanged 11C-ORM-13070 decreased from 81 ± 4 % of total radioactivity at 4 min after tracer injection to 23 ± 4 % at 60 min. At least one of the radioactive metabolites penetrated into red blood cells, while the parent tracer remained in plasma. The apparent elimination rate constant and corresponding half-life of unchanged 11C-ORM-13070 in arterial plasma were 0.0117 ± 0.0056 min−1 and 73.6 ± 35.8 min, respectively. The organs with the highest absorbed doses were the liver (12 μSv/MBq), gallbladder wall (12 μSv/MBq) and pancreas (9.1 μSv/MBq). The mean effective dose was 3.9 μSv/MBq, with a range of 3.6 – 4.2 μSv/MBq.

Conclusion

11C-ORM-13070 was rapidly metabolized in human subjects after intravenous injection. The effective radiation dose of 11C-ORM-13070 was in the same range as that of other 11C-labelled brain receptor tracers. An injection of 500 MBq of 11C-ORM-13070 would expose a subject to 2.0 mSv of radiation. This supports the use of 11C-ORM-13070 in repeated PET scans, for example, in receptor occupancy trials with novel drug candidates.

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Acknowledgments

The professional assistance of the staff at Turku PET Centre is greatly appreciated. Dr. Robert M. Badeau, Ph.D., of the Turku University Language Centre provided excellent assistance with the linguistic editing of the manuscript.

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Authors and Affiliations

  1. Turku PET Centre, University of Turku and Turku University Hospital, FI-20521, Turku, Finland

    Pauliina Luoto, Sami Suilamo, Vesa Oikonen, Eveliina Arponen, Semi Helin, Jere Virta, Kirsi Virtanen, Anne Roivainen & Juha O. Rinne

  2. Department of Oncology and Radiotherapy, Turku University Hospital, Turku, Finland

    Sami Suilamo

  3. Orion Pharma, Espoo and Turku, Finland

    Jukka Herttuainen, Johanna Hietamäki, Aila Holopainen, Juha Rouru & Jukka Sallinen

  4. Turku Imanet, GE Healthcare, Turku, Finland

    Marita Kailajärvi

  5. CRST, University of Turku, Turku, Finland

    Juha M. Peltonen, Mika Scheinin, Iina Volanen & Juha O. Rinne

  6. Unit of Clinical Pharmacology, TYKSLAB, Turku, Finland

    Juha O. Rinne

  7. Division of Clinical Neurosciences, University of Turku and Turku University Hospital, Turku, Finland

    Juha O. Rinne

Authors
  1. Pauliina Luoto
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  2. Sami Suilamo
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  3. Vesa Oikonen
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  4. Eveliina Arponen
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  5. Semi Helin
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  7. Johanna Hietamäki
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  8. Aila Holopainen
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  9. Marita Kailajärvi
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  10. Juha M. Peltonen
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  11. Juha Rouru
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  12. Jukka Sallinen
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  13. Mika Scheinin
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  14. Jere Virta
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  15. Kirsi Virtanen
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  16. Iina Volanen
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  17. Anne Roivainen
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  18. Juha O. Rinne
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Corresponding author

Correspondence to Juha O. Rinne.

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Luoto, P., Suilamo, S., Oikonen, V. et al. 11C-ORM-13070, a novel PET ligand for brain α2C-adrenoceptors: radiometabolism, plasma pharmacokinetics, whole-body distribution and radiation dosimetry in healthy men. Eur J Nucl Med Mol Imaging 41, 1947–1956 (2014). https://doi.org/10.1007/s00259-014-2782-y

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  • DOI: https://doi.org/10.1007/s00259-014-2782-y

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