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Test–retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant

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Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Objective

To evaluate the reproducibility of cerebral adenosine A2A receptor (A2AR) quantification using [11C]preladenant ([11C]PLN) and PET in a test–retest study.

Methods

Eight healthy male volunteers were enrolled. Dynamic 90 min PET scans were performed twice at the same time of the day to avoid the effect of diurnal variation. Subjects refrained from caffeine from 12 h prior to scanning, and serum caffeine was measured before radioligand injection. Arterial blood was sampled repeatedly during scanning and the fraction of the parent compound in plasma was determined. Total distribution volume (VT) was estimated using 1- and 2-tissue compartment models (1-TCM and 2-TCM, respectively) and Logan graphical analysis (Logan plot) (t* = 30 min). Plasma-free fraction (fP) of [11C]PLN was measured and used for correction of VT values. Distribution volume ratio (DVR) was calculated from VT of target and reference regions and obtained by noninvasive Logan graphical reference tissue model (LGAR) (t* = 30 min). Absolute test–retest variability (aTRV), and intra-class correlation coefficient (ICC) of VT and DVR were calculated as indexes of repeatability. Correlation between DVR and serum concentration of caffeine (a nonselective A2AR blocker) was analyzed by Pearson’s correlation analysis.

Results

Regional time–activity curves were well described by 2-TCM models. Estimation of VT by 2-TCM produced some erroneous values; therefore, the more robust Logan plot was selected as the appropriate model. Global mean aTRV was 20% for VT and 14% for VT/fP (ICC, 0.72 for VT and 0.87 for VT/fP). Global mean aTRV of DVR was 13% for Logan plot and 10% for LGAR (ICC, 0.70 for Logan plot and 0.81 for LGAR). DVR estimates using LGAR and Logan plot were in good agreement (r2 = 0.96). Coefficients of variation for VT, VT/fP, DVR (Logan plot), and DVR (LGAR) were 47%, 47%, 27%, and 18%, respectively. Despite low serum caffeine levels, significant concentration-dependent effects on [11C]PLN binding to target regions were observed (p < 0.01).

Conclusions

In this study, moderate test–retest reproducibility and large inter-subject differences were observed with [11C]PLN PET, possibly attributable to competition by baseline amount of caffeine. Analysis of plasma caffeine concentration is recommended during [11C]PLN PET studies.

Trial registration

UMIN000030040.

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Availability of data and materials

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

References

  1. van Waarde A, Dierckx RAJO, Zhou X, Khanapur S, Tsukada H, Ishiwata K, et al. Potential therapeutic application of adenosine A2A receptor ligands and opportunities for A2A receptor imaging. Med Res Rev. 2018;38:5–56.

    Article  Google Scholar 

  2. Paton DM. Istradefylline: adenosine A2A receptor antagonist to reduce “off” time in Parkinson’s disease. Drugs Today (Barc). 2020;56:125–34.

    Article  CAS  Google Scholar 

  3. Naganawa M, Kimura Y, Mishina M, Manabe Y, Chihara K, Oda K, et al. Quantification of adenosine A2A receptors in the human brain using [11C]TMSX and positron emission tomography. Eur J Nucl Med Mol Imaging. 2007;34:679–87.

    Article  CAS  Google Scholar 

  4. Brooks DJ, Doder M, Osman S, Luthra SK, Hirani E, Hume S, et al. Positron emission tomography analysis of [11C]KW-6002 binding to human and rat adenosine A2A receptors in the brain. Synapse. 2008;62:671–81.

    Article  CAS  Google Scholar 

  5. Ramlackhansingh AF, Bose SK, Ahmed I, Turkheimer FE, Pavese N, Brooks DJ. Adenosine 2A receptor availability in dyskinetic and nondyskinetic patients with Parkinson disease. Neurology. 2011;76:1811–6.

    Article  CAS  Google Scholar 

  6. Sakata M, Ishibashi K, Imai M, Wagatsuma K, Ishii K, Zhou X, et al. Initial evaluation of an adenosine A2A receptor ligand, 11C-preladenant, in healthy human subjects. J Nucl Med. 2017;58:1464–70.

    Article  CAS  Google Scholar 

  7. Barret O, Hannestad J, Vala C, Alagille D, Tavares A, Laruelle M, et al. Characterization in humans of 18F-MNI-444, a PET radiotracer for brain adenosine 2A receptors. J Nucl Med. 2015;56:586–91.

    Article  CAS  Google Scholar 

  8. Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Occupancy of adenosine A2A receptors by istradefylline in patients with Parkinson’s disease using 11C-preladenant PET. Neuropharmacology. 2018;143:106–12.

    Article  CAS  Google Scholar 

  9. Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Adenosine A2A receptor occupancy by long-term istradefylline administration in Parkinson’s disease. Mov Disord. 2021;38:268–9.

    Article  Google Scholar 

  10. Wagatsuma K, Miwa K, Sakata M, Oda K, Ono H, Kameyama M, et al. Comparison between new-generation SiPM-based and conventional PMT-based TOF-PET/CT. Phys Med. 2017;42:203–10.

    Article  Google Scholar 

  11. Toyohara J, Yamamoto H, Tago T. Searching for diagnostic properties of novel fluorine-18-labeled D-allose. Ann Nucl Med. 2019;33:855–65.

    Article  CAS  Google Scholar 

  12. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurement applied to [N-11C-methyl]-(–)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab. 1990;10:740–7.

    Article  CAS  Google Scholar 

  13. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL. Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab. 1996;16:834–40.

    Article  CAS  Google Scholar 

  14. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rather reliability. Psychol Bull. 1979;86:420–8.

    Article  CAS  Google Scholar 

  15. Motulsky HJ, Brown RE. Detecting outliers when fitting data with nonlinear regression—a new method based on robust nonlinear regression and false discovery rate. BMC Bioinformatics. 2006;7:123.

    Article  Google Scholar 

  16. Zhou X, Khanapur S, de Jong JR, Willemsen ATM, Dierckx RAJO, Elsinga PH, et al. In vivo evaluation of [11C]preladenant positron emission tomography for quantification of adenosine A2A receptors in the rat brain. J Cereb Blood Flow Metab. 2017;37:577–89.

    Article  CAS  Google Scholar 

  17. Eckelman WC, Kilbourn MR, Mathis CA. Specific to nonspecific binding in radiopharmaceutical studies: it’s not so simple as it seems! Nucl Med Biol. 2009;36:235–7.

    Article  CAS  Google Scholar 

  18. Zhou X, Boellaard R, Ishiwata K, Sakata M, Dierckx RAJO, de Joung JR, et al. In vivo evaluation of 11C-preladenant for PET imaging of adenosine A2A receptors in conscious monkey. J Nucl Med. 2017;58:762–7.

    Article  CAS  Google Scholar 

  19. Ottoy J, De Picker L, Verhaeghe J, Deleye S, Wyffels L, Kosten L, et al. 18F-PBR111 PET imaging in healthy controls and schizophrenia: test–retest reproducibility and quantification of neuroinflammation. J Nucl Med. 2018;59:1267–74.

    Article  CAS  Google Scholar 

  20. Mase H, Tanaka A, Sasou T, Nozaki A, Asai S, Miyachi H. Simultaneous measurement of concentrations of caffeine and ibuprofen in blood by LC-MS/MS and pharmacokinetic analysis after oral intake of canned coffee. Jpn J Med Technol. 2015;64:413–20.

    Google Scholar 

  21. Jacobson KA, Gao Z-G, Matricon P, Eddy MT, Carisson J. Adenosine A2A receptor antagonists: from caffeine to selective non-xanthines. Br J Pharmacol. 2020. https://doi.org/10.1111/bph.15103.

    Article  PubMed  PubMed Central  Google Scholar 

  22. White JR Jr, Padowski JM, Zhong Y, Chen G, Luo S, Lazarus P, et al. Pharmacokinetic analysis and comparison of caffeine administered rapidly or slowly in coffee chilled or hot versus chilled energy drink in healthy young adults. Clin Toxicol (Phila). 2016;54:308–12.

    Article  Google Scholar 

  23. Caffeine for the Sustainment of Mental Task, Performance: Formulations for Military Operations. Committee on Military Nutrition Research, Food, and Nutrition Board. National Academy of Sciences; [cited 2015 Oct]. Available from: https://iom.nationalacademies.org/Reports/2001/Caffeine-for-the-Sustainment-of-Mental-Task-Performance-Formulations-for-Military-Operations.aspx. Accessed 8 June 2021.

  24. Elmenhorst D, Meyer PT, Matusch A, Winz OH, Bauer A. Caffeine occupancy of human cerebral A1 adenosine receptors: in vivo quantification with 18F-CPFPX and PET. J Nucl Med. 2012;53:1723–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Mr. Masanari Sakai and Mr. Kosuke Nishino for technical support with cyclotron operation and radiosynthesis, Ms. Kimiko Yokoyama for care of the subjects during PET scanning, and Ms. Airin Onishi for coordination of the clinical study.

Funding

This work was supported in part by Grants-in-Aid for Scientific Research (B) No. 16H05396 (K.I.) and (C) No. 21K07663 (J.T.) from the Japan Society for the Promotion of Science.

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Authors and Affiliations

  1. Research Team for Neuroimaging, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakae-cho, Itabashi-ku, Tokyo, 173-0015, Japan

    Jun Toyohara, Muneyuki Sakata, Kei Wagatsuma, Tetsuro Tago, Kenji Ishibashi, Kenji Ishii & Kiichi Ishiwata

  2. School of Allied Health Science, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa, 252-0373, Japan

    Kei Wagatsuma

  3. Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands

    Philip Elsinga

  4. Institute of Cyclotron and Drug Discovery Research, Southern Tohoku Research Institute for Neuroscience, 7-115 Yatsuyamada, Koriyama, Fukushima, 963-8563, Japan

    Kiichi Ishiwata

  5. Department of Biofunctional Imaging, Fukushima Medical University, 1 Hikariga-oka, Fukushima, 960-1295, Japan

    Kiichi Ishiwata

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  1. Jun Toyohara
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  2. Muneyuki Sakata
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Correspondence to Jun Toyohara.

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The authors have no relevant financial or non-financial interests to disclose.

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All procedures performed in studies involving human participants were approved by the Ethics Committee of the Tokyo Metropolitan Institute of Gerontology (H28-46), and in accordance with the principles of the 1964 Declaration of Helsinki and its later amendments.

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Written informed consent was obtained from all individual participants prior to their inclusion in the study.

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Toyohara, J., Sakata, M., Wagatsuma, K. et al. Test–retest reproducibility of cerebral adenosine A2A receptor quantification using [11C]preladenant. Ann Nucl Med 36, 15–23 (2022). https://doi.org/10.1007/s12149-021-01678-5

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  • DOI: https://doi.org/10.1007/s12149-021-01678-5

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