Skip to main content
Log in

Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

In a previous PET study on norepinephrine transporter (NET) occupancy in the nonhuman primate brain, the relationship between NET occupancy and atomoxetine plasma concentration, and occupancies among different brain regions, were not demonstrated adequately. It may therefore be difficult to translate the results to the clinical situations. In the present study, the detailed change of NET occupancy was investigated among a wider range of doses in a more advanced manner.

Methods

Two rhesus monkeys were examined using a high-resolution PET system with (S,S)-[18F]FMeNER-D2 under baseline conditions and after steady-state infusion of different doses of atomoxetine (0.003 to 0.12 mg/kg per hour). NET occupancy of the thalamus, brainstem and anterior cingulate cortex was calculated using BPND obtained with the simplified reference tissue model.

Results

NET occupancy increased regionally and uniformly as the plasma concentration of atomoxetine increased. The estimated Kd value (the amount to occupy 50% of NET) in the thalamus was 16 ng/ml.

Conclusion

The results indicate that clinical doses of atomoxetine would occupy NET almost completely.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Tejani-Butt SM, Yang J, Zaffar H. Norepinephrine transporter sites are decreased in the locus coeruleus in Alzheimer’s disease. Brain Res 1993;631:147–50. doi:10.1016/0006-8993(93)91201-3.

    Article  PubMed  CAS  Google Scholar 

  2. Klimek V, Stockmeier C, Overholser J, Meltzer HY, Kalka S, Dilley G, et al. Reduced levels of norepinephrine transporters in the locus coeruleus in major depression. J Neurosci 1997;17:8451–8.

    PubMed  CAS  Google Scholar 

  3. Li W, Knowlton D, Van Winkle DM, Habecker BA. Infarction alters both the distribution and noradrenergic properties of cardiac sympathetic neurons. Am J Physiol Heart Circ Physiol 2004;286:H2229–H2236. doi:10.1152/ajpheart.00768.2003.

    Article  PubMed  CAS  Google Scholar 

  4. Bobb AJ, Addington AM, Sidransky E, Gornick MC, Lerch JP, Greenstein DK, et al. Support for association between ADHD and two candidate genes: NET1 and DRD1. Am J Med Genet B Neuropsychiatr Genet 2005;134:67–72. doi:10.1002/ajmg.b.30142.

    Google Scholar 

  5. Berzewski H, Van Moffaert M, Gagiano CA. Efficacy and tolerability of reboxetine compared with imipramine in a double-blind study in patients suffering from major depressive episodes. Eur Neuropsychopharmacol 1997;7(Suppl 1):S37–47. doi:10.1016/S0924-977X(97)00418-5.

    Article  PubMed  CAS  Google Scholar 

  6. Massana J. Reboxetine versus fluoxetine: an overview of efficacy and tolerability. J Clin Psychiatry 1998;59(Suppl 14):8–10.

    PubMed  CAS  Google Scholar 

  7. Spencer T, Biederman J, Wilens T, Prince J, Hatch M, Jones J, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693–5.

    PubMed  CAS  Google Scholar 

  8. Michelson D, Faries D, Wernicke J, Kelsey D, Kendrick K, Sallee FR, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics 2001;108:E83. doi:10.1542/peds.108.5.e83.

    Article  PubMed  CAS  Google Scholar 

  9. Bymaster FP, Katner JS, Nelson DL, Hemrick-Luecke SK, Threlkeld PG, Heiligenstein JH, et al. Atomoxetine increases extracellular levels of norepinephrine and dopamine in prefrontal cortex of rat: a potential mechanism for efficacy in attention deficit/hyperactivity disorder. Neuropsychopharmacology 2002;27:699–711. doi:10.1016/S0893-133X(02)00346-9.

    Article  PubMed  CAS  Google Scholar 

  10. Schou M, Halldin C, Sovago J, Pike VW, Gulyas B, Mozley PD, et al. Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[11C]MeNER. Nucl Med Biol 2003;30:707–14. doi:10.1016/S0969-8051(03)00079-9.

    Article  PubMed  CAS  Google Scholar 

  11. Ding YS, Lin KS, Garza V, Carter P, Alexoff D, Logan J, et al. Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs. Synapse 2003;50:345–52. doi:10.1002/syn.10281.

    Article  PubMed  CAS  Google Scholar 

  12. Schou M, Halldin C, Sovago J, Pike VW, Hall H, Gulyas B, et al. PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse 2004;53:57–67. doi:10.1002/syn.20031.

    Article  PubMed  CAS  Google Scholar 

  13. Seneca N, Gulyas B, Varrone A, Schou M, Airaksinen A, Tauscher J, et al. Atomoxetine occupies the norepinephrine transporter in a dose-dependent fashion: a PET study in nonhuman primate brain using (S,S)-[18F]FMeNERD2. Psychopharmacology (Berl) 2006;188:119–27. doi:10.1007/s00213-006-0483-3.

    Article  CAS  Google Scholar 

  14. Sureau FC, Reader AJ, Comtat C, Leroy C, Ribeiro MJ, Buvat I, et al. Impact of image-space resolution modeling for studies with the high-resolution research tomograph. J Nucl Med 2008;49:1000–8. doi:10.2967/jnumed.107.045351.

    Article  PubMed  Google Scholar 

  15. Varrone A, Sjoholm N, Gulyas B, Halldin C, Farde L. Advancement in PET quantification using 3D-OP-OSEM PSF reconstruction with the HRRT. Neuroimage 2008;41:T85.

    Article  Google Scholar 

  16. Hong IK, Chung ST, Kim HK, Kim YB, Son YD, Cho ZH. Ultra fast symmetry and SIMD-based projection-backprojection (SSP) algorithm for 3-D PET image reconstruction. IEEE Trans Med Imaging 2007;26:789–803.

    Article  PubMed  CAS  Google Scholar 

  17. Clark JD, Gebhart GF, Gonder JC, Keeling ME, Kohn DF. Special Report: The 1996 Guide for the Care and Use of Laboratory Animals. ILAR J 1997;38:41–8.

    PubMed  Google Scholar 

  18. Karlsson P, Farde L, Halldin C, Swahn CG, Sedvall G, Foged C, et al. PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor. Psychopharmacology (Berl) 1993;113:149–56.

    Article  CAS  Google Scholar 

  19. Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–8.

    Article  PubMed  CAS  Google Scholar 

  20. Ichise M, Liow JS, Lu JQ, Takano A, Model K, Toyama H, et al. Linearized reference tissue parametric imaging methods: application to [11C]DASB positron emission tomography studies of the serotonin transporter in human brain. Cereb Blood Flow Metab 2003;23:1096–112.

    Google Scholar 

  21. Swanson LW, Hartman BK. The central adrenergic system. An immunofluorescence study of the location of cell bodies and their efferent connections in the rat utilizing dopamine-beta-hydroxylase as a marker. J Comp Neurol 1975;163:467–505.

    Article  PubMed  CAS  Google Scholar 

  22. Schou M, Halldin C, Pike VW, Mozley PD, Dobson D, Innis RB, et al. Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol 2005;15:517–20.

    Article  PubMed  CAS  Google Scholar 

  23. Farde L, Wiesel FA, Nordström AL, Sedvall G. D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berl) 1989;99:S28–31.

    Article  Google Scholar 

  24. Witcher JW, Long A, Smith B, Sauer JM, Heilgenstein J, Wilens T, et al. Atomoxetine pharmacokinetics in children and adolescents with attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 2003;13:53–63.

    Article  PubMed  Google Scholar 

  25. Takano A, Suhara T, Ikoma Y, Yasuno F, Maeda J, Ichimiya T, et al. Estimation of the time-course of dopamine D2 receptor occupancy in living human brain from plasma pharmacokinetics of antipsychotics. Int J Neuropsychopharmacol 2004;7:19–26.

    Article  PubMed  CAS  Google Scholar 

  26. Takano A, Gulyás B, Varrone A, Karlsson P, Schou M, Airaksinen AJ, et al. Imaging the norepinephrine transporter with positron emission tomography: initial human studies with (S,S)-[18F]FMeNER-D2. Eur J Nucl Med Mol Imaging 2008;35:153–7.

    Article  PubMed  CAS  Google Scholar 

  27. Takano A, Halldin C, Varrone A, Karlsson P, Sjöholm N, Stubbs JB, et al. Biodistribution and radiation dosimetry of the norepinephrine transporter radioligand (S,S)-[18F]FMeNER-D2: a human whole-body PET study. Eur J Nucl Med Mol Imaging 2008;35:630–6.

    Article  PubMed  CAS  Google Scholar 

  28. Takano A, Varrone A, Gulyás B, Karlsson P, Tauscher J, Halldin C. Mapping of the norepinephrine transporter in the human brain using PET with (S,S)-[18F]FMeNER-D2. Neuroimage 2008;42:474–82.

    Article  PubMed  Google Scholar 

  29. Arakawa R, Okumura M, Ito H, Seki C, Takahashi H, Takano H, et al. Quantitative analysis of norepinephrine transporter in the human brain using PET with (S,S)-18F-FMeNER-D2. J Nucl Med 2008;49:1270–6.

    Article  PubMed  Google Scholar 

  30. Kubota T, Hirota K, Yoshida H, Takahashi S, Anzawa N, Ohkawa H, et al. Effects of sedatives on noradrenaline release from the medial prefrontal cortex in rats. Psychopharmacology (Berl) 1999;146:335–8.

    Article  CAS  Google Scholar 

  31. Anzawa N, Kushikata T, Ohkawa H, Yoshida H, Kubota T, Matsuki A. Increased noradrenaline release from rat preoptic area during and after sevoflurane and isoflurane anesthesia. Can J Anaesth 2001;48:462–5.

    Article  PubMed  CAS  Google Scholar 

  32. Kushikata T, Hirota K, Kotani N, Yoshida H, Kudo M, Matsuki A. Isoflurane increases norepinephrine release in the rat preoptic area and the posterior hypothalamus in vivo and in vitro: relevance to thermoregulation during anesthesia. Neuroscience 2005;131:79–86.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Gudrun Nylen and the members of the Karolinska PET group for their assistance in the PET experiments.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Akihiro Takano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takano, A., Gulyás, B., Varrone, A. et al. Saturated norepinephrine transporter occupancy by atomoxetine relevant to clinical doses: a rhesus monkey study with (S,S)-[18F]FMeNER-D2 . Eur J Nucl Med Mol Imaging 36, 1308–1314 (2009). https://doi.org/10.1007/s00259-009-1118-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-009-1118-9

Keywords

Navigation