Skip to main content

Advertisement

SpringerLink
Log in

Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study

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

Abstract

Purpose

The dopamine transporter (DAT) is a plasma membrane protein of central interest in the pathophysiology of neuropsychiatric disorders and is known to be a target for psychostimulant drugs. [11C]PE2I is a new radioligand which binds selectively and with moderate affinity to central DAT, as has been demonstrated in vitro by autoradiography and in vivo by positron emission tomography (PET). The aims of the present PET study were to quantify regional [11C]PE2I binding to DAT in the human brain and to compare quantitative methods with regard to suitability for applied clinical studies.

Methods

One PET measurement was performed in each of eight healthy male subjects. The binding potential (BP) values were obtained by applying kinetic compartment analysis, which uses the metabolite-corrected arterial plasma curve as an input function. They were compared with the BP values quantified by two reference tissue approaches, using cerebellum as a reference region representing free and non-specific radioligand binding.

Results

The radioactivity concentration was highest in the striatum, lower in the midbrain and very low in the cerebellum. The regional [11C]PE2I binding could be interpreted by kinetic compartment models. However, the BP values in the striatum obtained by the compartment analyses were about 30% higher than the BP values obtained using reference tissue methods. We suggest that the difference may be explained by the inaccurate metabolite correction, small amounts of radioactive metabolites that could account for the presence of non-specific binding in the cerebellum and insufficient data acquisition time.

Conclusion

The reference methods may be used to quantify [11C]PE2I binding in clinical studies, assuming that non-specific binding in the cerebellum does not vary between subjects and that an extended data acquisition time is employed. Moreover, the study corroborates the previous observation that [11C]PE2I is advantageous for PET examination of DAT binding in the midbrain, a region from which dopaminergic innervation originates and which is of central interest for the pathophysiology of several neuropsychiatric disorders.

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
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Gulley JM, Zahniser NR. Rapid regulation of dopamine transporter function by substrates, blockers and presynaptic receptor ligands. Eur J Pharmacol 2003;31(479):139–152

    Article  CAS  Google Scholar 

  2. Antonini A, Moresco RM, Gobbo C, De Notaris R, Panzacchi A, Barone P, et al. The status of dopamine nerve terminals in Parkinson's disease and essential tremor: a PET study with the tracer [11-C]FE-CIT. Neurol Sci 2000;22:47–48

    Article  Google Scholar 

  3. Ginovart N, Lundin A, Farde L, Halldin C, Backman L, Swahn CG, et al. PET study of the pre- and post-synaptic dopaminergic markers for the neurodegenerative process in Huntington’s disease. Brain 1997;120:503–514

    Article  PubMed  Google Scholar 

  4. Laakso A, Bergman J, Haaparanta M, Vilkman H, Solin O, Syvalahti E, et al. Decreased striatal dopamine transporter binding in vivo in chronic schizophrenia. Schizophr Res 2001;52:115–120

    Article  PubMed  CAS  Google Scholar 

  5. Dresel S, Krause J, Krause K-H, LaFougere C, Brinkbäumer K, Kung HF, et al. Attention deficit hyperactivity disorder: binding of [99mTc]TRODAT-1 to the dopamine transporter before and after methylphenidate treatment. Eur J Nucl Med 2000;27:1518–1524

    Article  CAS  Google Scholar 

  6. Jucaite A, Fernell E, Halldin C, Forssberg H, Farde L. Reduced midbrain dopamine transporter binding in male adolescents with ADHD; association between striatal dopamine markers and motor hyperactivity. Biol Psychiatry 2005;57(3):229–238

    Article  PubMed  CAS  Google Scholar 

  7. Volkow ND, Wang GJ, Fowler JS, Logan J, Francheschi D, Maynard L, et al. Relationship between blockade of dopamine transporters by oral methylphenidate and increase in the extracellular dopamine: therapeutic implications. Synapse 2002;43:181–187

    Article  PubMed  CAS  Google Scholar 

  8. Emond P, Garreau L, Chalon S, Boazi M, Caillet M, Bricard J, et al. Synthesis and ligand binding of nortropane derivatives: N-substituted-2-carbomethoxy-3-(4’-iodophenyl)nortropane and N-(3-iodoprop-2E-enyl)-2-carbomethoxy-3-(3’,4’-disubstituted phenyl)nortropane. New affinity and selectivity compounds for the dopamine transporter. J Med Chem 1997;40:1366-1372

    Article  PubMed  CAS  Google Scholar 

  9. Hall H, Halldin C, Guilloteau D, Chalon S, Emond P, Besnard J, et al. Visualization of the dopamine transporter in the human brain postmortem with the new selective ligand [125I]PE2I. Neuroimage 1999;9:108–116

    Article  PubMed  CAS  Google Scholar 

  10. Halldin C, Erixon-Lindroth N, Pauli S, Chou YH, Okubo Y, Karlsson P, et al. [11C]PE2I—a highly selective radioligand for PET-examination of the dopamine transporter in monkey and human brain. Eur J Nucl Med Mol Imaging 2003;30:1220–1230

    Article  PubMed  CAS  Google Scholar 

  11. Frost JJ, Douglass KH, Mayberg HS, Dannals RF, Links JM, Wilson AA, et al. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab 1989;9:398–409

    PubMed  CAS  Google Scholar 

  12. Wong D, Gjedde A, Wagner H Jr. Quantification of neuroreceptors in the living human brain. I. Irreversible binding of ligands. J Cereb Blood Flow Metab 1986;6:137–146

    PubMed  CAS  Google Scholar 

  13. Mintun M, Raichle M, Kilbourn M, Wooten G, Welch M. A quantitative model for the in vivo assessment of drug binding sites with positron emission tomography. Ann Neurol 1984;15:217–227

    Article  PubMed  CAS  Google Scholar 

  14. Huang S, Barrio J, Phelps M. Neuroreceptor assay with positron emission tomography. Equilibrium versus dynamic approaches. J Cereb Blood Flow Metab 1986;6:515–521

    PubMed  CAS  Google Scholar 

  15. Caceci MS, Cacheris WP. Fitting curves to data, the Simplex algorithm in the answer. BYTE 1984;9:340–362

    Google Scholar 

  16. Perlmutter JS, Larson KB, Raichle ME, Markham J, Mintun MA, Kilbourn MR, et al. Strategies for in vivo measurement of receptor binding using positron emission tomography. J Cereb Blood Flow Metab 1986;6:154–169

    PubMed  CAS  Google Scholar 

  17. Farde L, Eriksson L, Blomquist G, Halldin C. Kinetic analysis of central [11C]raclopride binding to D2-dopamine receptors studied by PET—a comparison to the equilibrium analysis. J Cereb Blood Flow Metab 1989;9:696–708

    PubMed  CAS  Google Scholar 

  18. Koeppe RA, Holthoff VA, Frey KA, Kilbourn MR, Kuhl DE. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography. J Cereb Blood Flow Metab 1991;11:735–744

    PubMed  CAS  Google Scholar 

  19. Delforge J, Pappata S, Millet P, Samson Y, Bendriem B, Jobert A, Crouzel C, Syrota A. Quantification of benzodiazepine receptors in human brain using PET, [11C]flumazenil, and a single-experiment protocol. J Cereb Blood Flow Metab 1995;15:284–300

    PubMed  CAS  Google Scholar 

  20. Farde L, Ito H, Swahn CG, Pike VW, Halldin C. Quantitative analyses of carbonyl-carbon-11-WAY-100635 binding to central 5-hydroxytryptamine-1A receptors in man. J Nucl Med 1998;39:1965–1971

    PubMed  CAS  Google Scholar 

  21. Lammerstma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, et al. Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab 1996;16:42–52

    Article  PubMed  Google Scholar 

  22. Akaike H. A new look at the statistical model identification. IEEE Trans Automat Contr 1974;19:716–723

    Article  Google Scholar 

  23. Schwartz G. Estimating the dimension of a model. Ann Stat 1978;6:461–564

    Article  Google Scholar 

  24. Hawkins R, Phelps M, Huand S-C. Effects of temporal sampling, glucose metabolic rates, and disruptions of the blood-brain barrier on the FDG model with and without a vascular compartment. Studies in human brain tumours with PET. J Cereb Blood Flow Metab 1986;6:170–183

    PubMed  CAS  Google Scholar 

  25. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schyler DJ, et al. Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]-(-)-cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990;10:740–747

    PubMed  CAS  Google Scholar 

  26. Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996;4:153–155

    Article  PubMed  CAS  Google Scholar 

  27. Bergström M, Boëthius J, Eriksson L, Greitz T, Ribbe T, Widen L. Head fixation device for reproducible position alignment in transmission CT and positron emission tomography. J Comput Assist Tomogr 1981;5:136–141

    Article  PubMed  Google Scholar 

  28. Wienhard K, Dahlbom M, Eriksson L, Michel C, Bruckbauer T, Pietrzyk U, et al. The ECAT EXACT HR: performance of a new high resolution positron scanner. J Comput Assist Tomogr 1994;18:108–110

    Article  Google Scholar 

  29. Eriksson L, Holte S, Bohm C, Kesselberg M, Hovander B. Automated blood sampling systems for positron emission tomography. IEEE Trans Nucl Sci 1988;35:703–707

    Article  Google Scholar 

  30. Drebin RA, Carpenter L, Hanrahan P. Volume rendering. Comput Graph 1988;22:65–74

    Article  Google Scholar 

  31. Toga AW. Three dimentional neuro imaging. New York: Raven Press; 1990

    Google Scholar 

  32. Pauli S, Sedvall G. Three-dimensional visualization of the benzodiazepine receptor population within a living human brain using PET and MRI. Eur Arch Psychiatry Clin Neurosci 1997;247:61–70

    Article  PubMed  CAS  Google Scholar 

  33. Olsson H, Halldin C, Farde L. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. NeuroImage 2004;22:794–803

    Article  PubMed  Google Scholar 

  34. Tupala E, Kuikka JT, Hall H, Bergstrom K, Sarkioja T, Rasanen P, et al. Measurement of the striatal dopamine transporter density and heterogeneity in type 1 alcoholics using human whole hemisphere autoradiography. Neuroimage 2001;14:87–94

    Article  PubMed  CAS  Google Scholar 

  35. Ciliax BJ, Drash GW, Staley JK, Haber S, Mobley CJ, Miller GW, et al. Immunocytochemical localization of the dopamine transporter in human brain. J Comp Neurol 1999;21(409):38–56

    Article  Google Scholar 

  36. Halldin C, Gulyas B, Langer O, Farde L. Brain radioligands—state of art and new trends. Q J Nucl Med 2001;45:139–152

    PubMed  CAS  Google Scholar 

  37. Laruelle M, Slifstein M, Huang Y. Positron emission tomography: imaging and quantification of neurotransporter availability. Methods 2002;27:287–299

    Article  PubMed  CAS  Google Scholar 

  38. Chalon S, Emond P, Garreau L, Frangin Y, Mauclaire L, Guilloteau D, et al. Characterisation of the cocaine derivative PE2I, a high specific marker for imaging the dopamine transporter by SPECT. Eur J Nucl Med 1997;24:880

    Google Scholar 

  39. Gu XH, Zong R, Kula NS, Baldessarini RJ, Neumeyer JL. Synthesis and biological evaluation of a series of novel N- or O-fluoroalkyl derivatives of tropane: potential positron emission tomography (PET) imaging agents for the dopamine transporter. Bioorg Med Chem Lett 2001;11:3049–3053

    Article  PubMed  CAS  Google Scholar 

  40. Lundkvist C, Halldin C, Ginovart N, Swahn CG, Farde L. [18F] beta-CIT-FP is superior to [11C] beta-CIT-FP for quantitation of the dopamine transporter. Nucl Med Biol 1997;24:621–627

    Article  PubMed  CAS  Google Scholar 

  41. Karlsson P, Sedvall G, Halldin C, Swahn CG, Farde L. Evaluation of SCH 39166 as PET ligand for central D1 dopamine receptor binding and occupancy in man. Psychopharmacology (Berl) 1995;121:300–308

    Article  CAS  Google Scholar 

  42. Farde L, Hall H, Ehrin E, Sedvall G. Quantitative analysis of D2 dopamine receptor binding in the living human brain by PET. Science 1986;231(4735):258–261

    Article  PubMed  CAS  Google Scholar 

  43. Madras BK, Gracz LM, Fahey MA, Elmaleh D, Meltzer PC, Liang AY, et al. Altropane, a SPECT or PET imaging probe for dopamine neurons: III. Human dopamine transporter in postmortem normal and Parkinson's diseased brain. Synapse 1998;29:116–127

    Article  PubMed  CAS  Google Scholar 

  44. Hurley MJ, Mash DC, Jenner P. Markers for dopaminergic neurotransmission in the cerebellum in normal individuals and patients with Parkinson’s disease examined by RT-PCR. Eur J Neurosci 2003;18:2668–2672

    Article  PubMed  Google Scholar 

  45. Schollborn-Peyronneau M, Pruvost A, Kuhnast B, Coulon C, Ottaviani M, Emond P, et al. Metabolism of PE2I and 11C-PE2I, a high selective ligand for PET examination of the dopamine transporter. J Nucl Med 2005;346:347

    Google Scholar 

  46. Farde L, Hall H, Pauli S, Halldin C. Variability in D2-dopamine receptor density and affinity: a PET study with [11C]raclopride in man. Synapse 1995;10:200–208

    Article  Google Scholar 

  47. Pinborg LH, Videbaek C, Svarer C, Yndgaard S, Paulson OB, Knudsen GM. Quantification of [123I]PE2I binding to dopamine transporters with SPET. Eur J Nucl Med Mol Imaging 2002;29:623–631

    Article  PubMed  CAS  Google Scholar 

  48. Olsson H, Halldin C, Swahn CG, Farde L. Quantification of [11C]FLB 457 binding to extrastriatal dopamine receptors in the human brain. J Cereb Blood Flow Metab 1999;19(10):1164–1173

    Article  PubMed  CAS  Google Scholar 

  49. Olsson H, Halldin C, Farde L. Differentiation of extrastriatal dopamine D2 receptor density and affinity in the human brain using PET. Neuroimage 2004;22(2):794–803

    Article  Google Scholar 

  50. Slifstein M, Laruelle M. Effects of statistical noise on graphic analysis of PET neuroreceptor studies. J Nucl Med 2000;41:2083–2088

    PubMed  CAS  Google Scholar 

  51. Moore RY. Organization of midbrain dopamine systems and the pathophysiology of Parkinson’s disease. Parkinsonism Relat Disord Suppl 2003;2:S65–S71

    Article  Google Scholar 

  52. Poyot T, Conde F, Gregoire MC, Frouin V, Coulon C, Fuseau C, et al. Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-L-dopa. J Cereb Blood Flow Metab 2001;21:782–792

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Swedish Research Council (09114/15A). Aurelija Jucaite was sponsored by The Frimurare Barnhuset, Sunnerdahl Handikapp, Sällskapet Barnavård, Professor Bror Gardelius Memorial Foundation. The authors would like to thank the members of the Stockholm PET group, and in particular Kjerstin Lind and Arsalan Amir, for their participation in data acquisition and for their technical assistance.

Author information

Authors and Affiliations

  1. Psychiatry Section, Department of Clinical Neuroscience, Karolinska Institutet,, Stockholm, Sweden

    Hans Olsson, Stefan Pauli, Christer Halldin & Lars Farde

  2. Department of Woman and Child Health, Karolinska Institutet,, Stockholm, Sweden

    Aurelija Jucaite

  3. Division of Functional Imaging, Department of Sensory and Integrative Medicine, Niigata University Graduate School of Medicine and Dental Sciences,, Asahimachi-dori Niigata, Japan

    Ikuo Odano

Authors
  1. Aurelija Jucaite
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ikuo Odano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans Olsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Pauli
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Christer Halldin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lars Farde
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Aurelija Jucaite.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jucaite, A., Odano, I., Olsson, H. et al. Quantitative analyses of regional [11C]PE2I binding to the dopamine transporter in the human brain: a PET study. Eur J Nucl Med Mol Imaging 33, 657–668 (2006). https://doi.org/10.1007/s00259-005-0027-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-005-0027-9

Keywords

Search

Navigation