Skip to main content
SpringerLink
Log in

Synthesis and Positron Emission Tomography Evaluation of Three Norepinephrine Transporter Radioligands: [C-11]Desipramine, [C-11]Talopram and [C-11]Talsupram

  • Original Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Desipramine (DMI), talopram and talsupram, three of the most potent norepinephrine transporter (NET) inhibitors reported to date, were radiolabeled in high yields and at high specific radioactivity (58–75 GBq/μmol) by the methylation of nor-precursors with [C-11]methyl triflate. The regional brain distribution of each radioligand following intravenous injection into cynomolgus monkey was examined in vivo with positron emission tomography (PET). For all three radioligands, the regional brain distribution of radioactivity was slightly heterogeneous, with higher uptake of radioactivity in the mesencephalon, thalamus and lower brainstem than in striatum. The rank order of maximal brain radioactivity (as percentage of injected dose) was [11C]DMI (2.7%) > [11C]talsupram (1.3%) > [11C]talopram (0.7%). The appearance of radioactive metabolites in plasma was similar for each radioligand (75–85% of radioactivity in plasma at 45 min). These metabolites were all more polar than their parent radioligand. The data show that these radioligands are inferior to existing radioligands for the study of brain NET with PET in vivo.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Notes

  1. It should be noted that in some cases the brain uptake of some PET radioligands in non-human species may be enhanced by using P-glycoprotein modulators [25, 26]. However, this approach has not yet been developed for application in human subjects.

References

  1. Halldin C, Gulyás B, Langer O, Farde L (2001) Brain radioligands– state of the art and new trends. Q J Nucl Med 45:139–152

    PubMed  CAS  Google Scholar 

  2. Haka MS, Kilbourn MR (1989). Synthesis and regional mouse brain distribution of [11C]nisoxetine, a norepinephrine transporter inhibitor. Nucl Med Biol 16:771–774

    CAS  Google Scholar 

  3. Schou M, Halldin C, Sóvágó J, Pike VW, Gulyás B, Mozley PD, Johnson DP, Hall H, Innis RB, Farde L (2003) Specific in vivo binding to the norepinephrine transporter demonstrated with the PET radioligand, (S,S)-[11C]MeNER. Nucl Med Biol 30:707–714

    Article  PubMed  CAS  Google Scholar 

  4. Wilson AA, Johnson DP, Mozley PD, Hussey D, Ginovart N, Nobrega J, Garcia A, Meyer J, Houle S (2003) Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter. Nucl Med Biol 30:85–92

    Article  PubMed  CAS  Google Scholar 

  5. Ding Y-S, Lin K-S, Garza V, Carter P, Alexoff D, Logan J, Shea C, Xu Y, King P (2003). Evaluation of a new norepinephrine transporter PET ligand in baboons, both in brain and peripheral organs. Synapse 50: 345–352

    Article  PubMed  CAS  Google Scholar 

  6. Schou M, Halldin C, Sovago J, Pike VW, Hall H, Gulyás B, Mozley PD, Dobson D, Shchukin E, Innis RB, Farde L (2004) PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse 53:57–67

    Article  PubMed  CAS  Google Scholar 

  7. Bowden CL, Schatzberg AF, Rosenbaum A, Contreras SA, Samson JA, Dessain E, Sayler M (1993) Fluoxetine and desipramine in major depressive disorder. J Clin Psychopharmacol 13:305–311

    Article  PubMed  CAS  Google Scholar 

  8. Bøgesø KP, Christiansen AV, Hyttel J, Liljefors T (1985) 3-Phenyl-1-indanamines. Potential antidepressant activity and potent inhibitors of dopamine, norepinephrine and serotonin uptake. J Med Chem 28:1817–1828

    Article  PubMed  Google Scholar 

  9. Hyttel J (1982) Citalopram—pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog Neuro-Psychopharmacol Biol Psychiatry 6:277–295

    Article  CAS  Google Scholar 

  10. Cusack B, Nelson A, Richelson E (1994) Binding of antidepressants to human brain receptors: Focus on newer generation compounds. Psychopharmacology (Berl) 114:559–565

    Article  CAS  Google Scholar 

  11. Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (1997) Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites. J Pharmacol Exp Ther 283:1305–1322

    PubMed  CAS  Google Scholar 

  12. Bäckström I, Marcusson J (1990) High- and low-affinity [3H]desipramine-binding sites in human postmortem brain tissue. Neuropsychobiology 23:68–73

    Article  PubMed  Google Scholar 

  13. Gross-Isseroff R, Israeli M, Biegon A (1988) Autoradiographic analysis of [3H]desmethylimipramine binding in the human brain postmortem. Brain Res 456:120–126

    Article  PubMed  CAS  Google Scholar 

  14. Van Dort ME, Kim J-H, Tluczek L, Wieland DM (1997) Synthesis of 11C-labeled desipramine and its metabolite 2-hydroxydesipramine: Potential radiotracers for PET studies of the norepinephrine transporter. Nucl Med Biol 24:707–711

    Article  PubMed  Google Scholar 

  15. McConathy J, Owens MJ, Kilts CD, Malveaux EJ, Camp VM, Votaw JR, Nemeroff CB, Goodman MM (2004) Synthesis and biological evaluation of [11C]talopram and [11C]talsupram: Candidate PET ligands for the norepinephrine transporter. Nucl Med Biol 31:705–718

    Article  PubMed  CAS  Google Scholar 

  16. Sandell J, Langer O, Larsen P, Dolle F, Vaufrey F, Demphel S, Crouzel C, Halldin C (2000) Improved specific radioactivity of the PET radioligand [11C]FLB 457 by use of the GE medical systems PETtrace MeI MicroLab. J Labelled Compd Radiopharm 43:331–338

    Article  CAS  Google Scholar 

  17. Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, Heiss W (1994) The ECAT Exact HR: Performance of a new high resolution positron scanner. J Comput Assist Tomogr 18:110–118

    Article  PubMed  CAS  Google Scholar 

  18. Karlsson P, Farde L, Halldin C, Swahn C-G, Sedvall G, Foged C, Hansen K, Skrumsager B (1993) PET examination of [11C]NNC 687 and [11C]NNC 756 as new radioligands for the D1-dopamine receptor. Psychopharmacology 113:149–156

    Article  PubMed  CAS  Google Scholar 

  19. Charnay Y, Leger L, Vallet P, Hof P, Juovet M, Bouras C (1995) [3H]Nisoxetine binding sites in the cat brain: An autoradiographic study. Neuroscience 69:259–270

    Article  PubMed  CAS  Google Scholar 

  20. Donnan G, Kaczmarczyk S, Paxinos G, Chilco P, Kalnins R, Woodhouse D, Mendelsohn F (1991) Distribution of catecholaminergic uptake sites in human brain as determined by quantitative [3H]mazindol autoradiography. J Comp Neurol 304:419–434

    Article  PubMed  CAS  Google Scholar 

  21. Tejani-Butt S (1992) [3H]Nisoxetine: A radioligand for quantitation of norepinephrine uptake sites by autoradiography or by homogenate binding. J Pharm Exp Ther 260:427–436

    CAS  Google Scholar 

  22. Halldin C, Swahn C-G, Farde L, Sedvall G (1995) Radioligand disposition and metabolism. In: Comar D, (ed) PET for Drug Development and Evaluation. Academic Publishers: Kluwer, pp. 55–65

  23. Waterhouse RN (2003) Determination of lipophilicity and its use as a predictor of blood brain barrier penetration of molecular imaging agents. Mol Imaging Biol 5:376–389

    Article  PubMed  Google Scholar 

  24. pKa, LogD and Log P values were predicted with the Pallas 3.0 for Windows software

  25. Doze P, Van Waarde A, Elsinga PH, Hendrikse NH, Vaalburg W (2000) Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood–brain barrier. Synapse 36:66–74

    Article  PubMed  CAS  Google Scholar 

  26. Balle T, Halldin C, Andersen L, Alfrangis LH, Badolo L, Jensen K.G., Chou YW, Andersen K, Perregaard J, Farde L (2004) New α1-adrenoceptor antagonists derived from the antipsychotic sertindole—carbon-11 labelling and PET examination of brain uptake in the cynomolgus monkey. Nucl Med Biol 31:327–336

    Article  PubMed  CAS  Google Scholar 

  27. Hara K, Yanagihara N, Minami K, Ueno S, Toyohira Y, Sata T, Kawamura M, Bruss M, Bonisch H, Shigematsu A, Izumi F (1998) Ketamine interacts with the noradrenaline transporter at a site partly overlapping the desipramine binding site. N-S Arch Pharmacol 358:328–333

    Article  CAS  Google Scholar 

  28. Uryu K, Minami K, Yanagihara N, Hara K, Toyohira Y, Izumi F, Shigematsu A (2000) Inhibition by neuromuscular blocking drugs of norepinephrine transporter in cultured bovine adrenal medullary cells. Anesth Analg 91:546–551

    Article  PubMed  CAS  Google Scholar 

Download references

The authors would like to thank H. Lundbeck A/S for supplying the precursors and standards of talopram and talsupram. We are also grateful for the technical assistance of Mr. A Amir and Mr. P. Truong and the other members of the PET group at Karolinska Institutet. Mr. M Schou was supported by the Karolinska Institutet-National Institutes of Health graduate training partnership program. This work was also supported in part by the Intramural Research Program of the Natinal Institute of Health (National Institute of Mental Health).

Author information

Authors and Affiliations

  1. Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176, Stockholm, Sweden

    Magnus Schou MSc, Judit Sóvágó MD, Balázs Gulyás MD, PhD, Lars Farde MD, PhD & Christer Halldin PhD

  2. Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Building 10 Rm. B3 C346A, 10 Center Drive, Bethesda, MD, 20892-1003, USA

    Magnus Schou MSc & Victor W. Pike PhD

  3. H. Lundbeck A/S, Copenhagen, Denmark

    Klaus P. Bøgesø PhD

Authors
  1. Magnus Schou MSc
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Judit Sóvágó MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Victor W. Pike PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Balázs Gulyás MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Klaus P. Bøgesø PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars Farde MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christer Halldin PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Magnus Schou MSc.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schou, M., Sóvágó, J., Pike, V.W. et al. Synthesis and Positron Emission Tomography Evaluation of Three Norepinephrine Transporter Radioligands: [C-11]Desipramine, [C-11]Talopram and [C-11]Talsupram. Mol Imaging Biol 8, 1–8 (2006). https://doi.org/10.1007/s11307-005-0027-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-005-0027-y

Key words

Search

Navigation