Skip to main content

Advertisement

SpringerLink
Log in

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133)

  • Original Article
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson’s disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[18F] fluoropropyl-(+)-dihydrotetrabenazine ([18F]AV-133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [18F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [18F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism.

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

Similar content being viewed by others

References

  1. Lang AE, Lozano AM. Parkinson’s disease. N Engl J Med 1998, 339: 1044–1053.

    Article  CAS  PubMed  Google Scholar 

  2. Yuan H, Zhang ZW, Liang LW, Shen Q, Wang XD, Ren SM, et al. Treatment strategies for Parkinson’s disease. Neurosci Bull 2010, 26: 66–76.

    Article  CAS  PubMed  Google Scholar 

  3. Xia R, Mao ZH. Progression of motor symptoms in Parkinson’s disease. Neurosci Bull 2012, 28: 39–48.

    Article  PubMed  Google Scholar 

  4. Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM, et al. Chronic parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979, 1: 249–254.

    Article  CAS  PubMed  Google Scholar 

  5. Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ. A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 1983, 80: 4546–4550.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Bezard E, Imbert C, Deloire X, Bioulac B, Gross CE. A chronic MPTP model reproducing the slow evolution of Parkinson’s disease: evolution of motor symptoms in the monkey. Brain Res 1997, 766: 107–112.

    Article  CAS  PubMed  Google Scholar 

  7. Ravina B, Eidelberg D, Ahlskog JE, Albin RL, Brooks DJ, Carbon M, et al. The role of radiotracer imaging in Parkinson disease. Neurology 2005, 64: 208–215.

    Article  CAS  PubMed  Google Scholar 

  8. Villemagne V, Yuan J, Wong DF, Dannals RF, Hatzidimitriou G, Mathews WB, et al. Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C] WIN-35,428 positron emission tomography studies and direct in vitro determinations. J Neurosci 1998, 18: 419–427.

    CAS  PubMed  Google Scholar 

  9. Stoessl AJ, de la Fuente-Fernandez R. Dopamine receptors in Parkinson’s disease: imaging studies. Adv Neurol 2003, 91: 65–71.

    CAS  PubMed  Google Scholar 

  10. Brooks DJ. Imaging dopamine transporters in Parkinson’s disease. Biomark Med 2010, 4: 651–660.

    Article  CAS  PubMed  Google Scholar 

  11. Marije BV, Leenders KL. Putamen FDOPA uptake and its relationship tot cognitive functioning in PD. J Neurol Sci 2006, 248: 68–71.

    Article  Google Scholar 

  12. Seibyl JP, Marek K, Sheff K, Baldwin RM, Zoghbi S, Zea-Ponce Y, et al. Test/retest reproducibility of Iodine-123-βCIT SPECT brain measurement of dopamine transporters in Parkinson’s patients. J Nucl Med 1 1997, 38: 1453–1459.

    CAS  Google Scholar 

  13. Jennings DL, Seibyl JP, Oakes D, Eberly S, Murphy J, Marek K. 123I-β-CIT and single-photon emission computed tomographic imaging vs clinical evaluation in Parkinsonian syndrome: Unmasking an early diagnosis. Arch Neurol 2 2004, 61: 1224–1229.

    Google Scholar 

  14. Alexoff DL, Vaska P, Marsteller D, Gerasimov T, Li J, Logan J, et al. Reproducibility of 11C-raclopride binding in the rat brain measured with the microPET R4: effects of scatter correction and tracer specific activity. J Nucl Med 2003, 44: 815–822.

    CAS  PubMed  Google Scholar 

  15. Frey KA, Koeppe RA, Kilbourn MR, Vander Borght TM, Albin RL, Gilman S, et al. Presynaptic monoaminergic vesicles in Parkinson’s disease and normal aging. Ann Neurol 1996, 40: 873–884.

    Article  CAS  PubMed  Google Scholar 

  16. Vander Borght T, Kilbourn M, Desmond T, Kuhl D, Frey K. The vesicular monoamine transporter is not regulated by dopaminergic drug treatments. Eur J Pharmacol 1995, 294: 577–583.

    Article  Google Scholar 

  17. Vander Borght TM, Sima AAF, Kilbourn MR, Desmond TJ, Kuhl DE, Frey KA. [3H]methoxytetrabenazine: A high specific activity ligand for estimating monoaminergic neuronal integrity. Neuroscience 1995, 68: 955–962.

    Article  Google Scholar 

  18. Miller GW, Erickson JD, Perez JT, Penland SN, Mash DC, Rye DB, et al. Immunochemical analysis of vesicular monoamine transporter (VMAT2) protein in Parkinson’s disease. Exp Neurol 1999, 156: 138–148.

    Article  CAS  PubMed  Google Scholar 

  19. Chen MK, Kuwabara H, Zhou Y, Adams RJ, Brašić JR, McGlothan JL, et al. VMAT2 and dopamine neuron loss in a primate model of Parkinson’s disease. J Neurochem 2008, 105: 78–90.

    Article  CAS  PubMed  Google Scholar 

  20. Goswami R, Ponde DE, Kung MP, Hou C, Kilbourn MR, Kung HF. Fluoroalkyl derivatives of dihydrotetrabenazine as positron emission tomography imaging agents targeting vesicular monoamine transporters. Nucl Med Biol 2006, 33: 685–694.

    Article  CAS  PubMed  Google Scholar 

  21. Kilbourn M, Hockley B, Lee L, Hou C, Goswami R, Ponde D, et al. Pharmacokinetics of [18F]fluoroalkyl derivatives of dihydrotetrabenazine in rat and monkey brain. Nucl Med Biol 2007, 34: 233–237.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Chao KT, Tsao HH, Weng YH, Hsiao IT, Hsieh CJ, Wey SP, et al. Quantitative analysis of binding sites for 9-fluoropropyl-(+)-dihydrotetrabenazine ([18F]AV-133) in a MPTP-lesioned PD mouse model. Synapse 2012, 66: 823–831.

    Article  CAS  PubMed  Google Scholar 

  23. Okamura N, Villemagne VL, Drago J, Pejoska S, Dhamija RK, Mulligan RS, et al. In vivo measurement of vesicular monoamine transporter type 2 density in parkinson disease with 18F-AV-133. J Nucl Med 2010, 51: 223–228.

    Article  PubMed  Google Scholar 

  24. Zhu L, Liu Y, Plossl K, Lieberman B, Liu J, Kung HF. An improved radiosynthesis of [18F]AV-133: a PET imaging agent for vesicular monoamine transporter 2. Nucl Med Biol 2010, 37: 133–141.

    Article  CAS  PubMed  Google Scholar 

  25. Zhu L, Qiao H, Lieberman BP, Wu J, Liu Y, Pan Z, et al. Imaging of VMAT2 binding sites in the brain by 18F-AV-133: The effect of a pseudo-carrier. Nucl Med Biol 2012, 39: 897–904.

    Article  CAS  PubMed  Google Scholar 

  26. Yokoyama C, Yamanaka H, Onoe K, Kawasaki A, Nagata H, Shirakami K, et al. Mapping of serotonin transporters by positron emission tomography with [11C]DASB in conscious common marmosets: Comparison with rhesus monkeys. Synapse 2010, 64: 594–601.

    Article  CAS  PubMed  Google Scholar 

  27. Benamer HTS, Patterson J, Wyper DJ, Hadley DM, Macphee GJA, Grosset DG. Correlation of Parkinson’s disease severity and duration with 123I-FP-CIT SPECT striatal uptake. Mov Disord 2000, 15: 692–698.

    Article  CAS  PubMed  Google Scholar 

  28. Walker MD, Dinelle K, Kornelsen R, McCormick S, Mah C, Holden JE, et al. In vivo measurement of LDOPA uptake, dopamine reserve and turnover in the rat brain using [18F] FDOPA PET. J Cereb Blood Flow Metab 2012: 1–8.

    Google Scholar 

  29. Topping GJ, Dinelle K, Kornelsen R, McCormick S, Holden JE, Sossi V. Positron emission tomography kinetic modeling algorithms for small animal dopaminergic system imaging. Synapse 2010, 64: 200–208.

    Article  CAS  PubMed  Google Scholar 

  30. Kurlan R, Kim MH, Gash DM. The time course and magnitude of spontaneous recovery of parkinsonism produced by intracarotid administration of 1-methyl-4-Phenyl-1,2,3,6-tetrahydropyridine to monkeys. Ann Neurol 1991, 29: 677–679.

    Article  CAS  PubMed  Google Scholar 

  31. Emborg ME, Ma SY, Mufson EJ, Levey AI, Taylor MD, Brown WD, et al. Age-related declines in nigral neuronal function correlate with motor impairments in rhesus monkeys. J Comp Neurol 1998, 401: 253–265.

    Article  CAS  PubMed  Google Scholar 

  32. Lin KJ, Weng YH, Wey SP, Hsiao IT, Lu CS, Skovronsky D, et al. Whole-body biodistribution and radiation dosimetry of 18F-FP-(+)-DTBZ (18F-AV-133): A novel vesicular monoamine transporter 2 imaging agent. J Nucl Med 2010, 51: 1480–1485.

    Article  CAS  PubMed  Google Scholar 

  33. Blesa J, Juri C, Collantes M, Peñuelas I, Prieto E, Iglesias E, et al. Progression of dopaminergic depletion in a model of MPTP-induced Parkinsonism in non-human primates. An 18F-DOPA and 11C-DTBZ PET study. Neurobiol Dis 2010, 38: 456–463.

    Article  CAS  PubMed  Google Scholar 

  34. Blesa J, Pifl C, Sánchez-González MA, Juri C, GarcÍa-Cabezas MA, Adánez R, et al. The nigrostriatal system in the presymptomatic and symptomatic stages in the MPTP monkey model: A PET, histological and biochemical study. Neurobiol Dis 2012, 48: 79–91.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China

    Yajing Liu, Feng Yue & Piu Chan

  2. Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China

    Yajing Liu, Feng Yue & Piu Chan

  3. Wincon Theracells Biotechnologies Inc., Nanning, 530003, China

    Rongping Tang, Guoxian Tao & Xiaomei Pan

  4. Key Laboratory of Radiopharmaceuticals, Beijing Normal University, Ministry of Education, Beijing, 100875, China

    Lin Zhu

  5. Department of Radiology, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Hank F. Kung

  6. Beijing Key Laboratory on Parkinson’s Disease, Beijing, 100053, China

    Feng Yue & Piu Chan

Authors
  1. Yajing Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Feng Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rongping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guoxian Tao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaomei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hank F. Kung
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Piu Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Piu Chan.

Additional information

These authors contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Liu, Y., Yue, F., Tang, R. et al. Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([18F]AV-133). Neurosci. Bull. 30, 409–416 (2014). https://doi.org/10.1007/s12264-013-1374-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-013-1374-3

Keywords

Search

Navigation