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Human Dosimetry of Carbon-11 Labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide Extrapolated from Whole-body Distribution Kinetics and Radiometabolism in Rats

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Abstract

Purpose

Carbon-11 labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide ([11C]PK11195) is a peripheral benzodiazepine receptor (PBR) antagonist that is used as a positron emission tomography (PET) radiopharmaceutical for neuroinflammatory imaging. This study was designed to investigate the radiation dosimetry of [11C]PK11195.

Procedures

Whole-body distribution kinetics of intravenously administered [11C]PK11195 in rats was assessed by means of dynamic PET imaging, and estimates for human radiation dosimetry were calculated. Rat plasma and various tissue homogenates obtained at different time points after intravenous injection of [11C]PK11195 were analyzed by reversed-phase gradient radio-HPLC method using online radiodetection. In addition, in vitro stability of [11C]PK11195 was determined in rat brain homogenate by incubation at +37°C.

Results

PET imaging of rats showed the highest radioactivity levels in heart, kidneys, thyroid gland, liver, and lungs. The radioactivity cleared rapidly from lungs and slowly from heart and liver. However, much of the radioactivity retained in kidneys, which was in concordance with the observed low urinary excretion of [11C]PK11195. Extrapolating from the rat data, the effective dose of [11C]PK11195 for a 70-kg man was estimated to be 4.2 ± 0.3 µSv/MBq. Five different radiometabolites were detected in rat plasma, and the level of intact [11C]PK11195 decreased from 80% ± 11% (mean ± SD) at 10 min to 44% ± 5% at 40 min after injection. In rat heart, brain, kidney, and lung homogenates, more than 90% of total radioactivity originated from intact [11C]PK11195. In liver, however, the amount of [11C]PK11195 was approximately 70% and decreased over time, indicating metabolism by liver enzymes.

Conclusions

[11C]PK11195 showed a fast uptake in many rat tissues and it was metabolized relatively fast in vivo, but not in brain in vitro. The estimated effective dose for humans speaks for the use of [11C]PK11195 in human PET imaging.

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Acknowledgments

We wish to thank our colleagues Tiina Ujula and Anu Autio for their excellent assistance in animal experiments. The study was conducted within the Finnish Center of Excellence in Molecular Imaging in Cardiovascular and Metabolic Research supported by the Academy of Finland, University of Turku, the Turku University Hospital, and the Åbo Akademi University. In addition, the study was financially supported by grants from the Academy of Finland (Nos. 205757 and 103032). Iina Laitinen is a PhD student supported by the National Drug Discovery Graduate School.

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Authors and Affiliations

  1. Turku PET Center, University of Turku, FI-20521, Turku, Finland

    Pauliina Luoto, Iina Laitinen, Sami Suilamo, Kjell Någren & Anne Roivainen

  2. Department of Oncology and Radiotherapy, Turku University Hospital, FI-20521, Turku, Finland

    Sami Suilamo

  3. Department of Clinical Physiology & Nuclear Medicine, Rigshospitalet, University of Copenhagen, PET & Cyclotron Unit, 3982, Blegdamsvej 9, DK-2100, Copenhagen, Denmark

    Kjell Någren

  4. Turku Center for Disease Modeling, University of Turku, FI-20521, Turku, Finland

    Anne Roivainen

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  1. Pauliina Luoto
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  2. Iina Laitinen
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Corresponding author

Correspondence to Anne Roivainen.

Additional information

Significance: although carbon-11-labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide ([11C]PK11195) is a widely used PET tracer for inflammation imaging in humans, the associated radiation load remains unknown. This is the first study to provide estimates of human radiation dosimetry.

A part of the paper has been presented in the EANM Annual Congress 2005 in Istanbul, Turkey, and the corresponding abstract was published in Eur J Nucl Med Mol Imaging 2005;32:P752.

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Luoto, P., Laitinen, I., Suilamo, S. et al. Human Dosimetry of Carbon-11 Labeled N-butan-2-yl-1-(2-chlorophenyl)-N-methylisoquinoline-3-carboxamide Extrapolated from Whole-body Distribution Kinetics and Radiometabolism in Rats. Mol Imaging Biol 12, 435–442 (2010). https://doi.org/10.1007/s11307-009-0293-1

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  • DOI: https://doi.org/10.1007/s11307-009-0293-1

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