SpringerLink
Log in

Quantification of SV2A Binding in Rodent Brain Using [18F]SynVesT-1 and PET Imaging

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

Abstract

Purpose

Synapse loss is a hallmark of Alzheimer’s disease (AD) and correlates with cognitive decline. The validation of a noninvasive in vivo imaging approach to quantify synapse would greatly facilitate our understanding of AD pathogenesis and assist drug developments for AD. As animal models of neurodegenerative and neuropsychiatric disorders play a critical role in the drug discovery and development process, a robust, objective, and translational method for quantifying therapeutic drug efficacy in animal models will facilitate the drug development process. In this study, we tested the quantification reliability of the SV2A PET tracer, [18F]SynVesT-1, in a mouse model of AD (APP/PS1) and wild-type controls, and developed a simplified quantification method to facilitate large cohort preclinical imaging studies.

Procedures

We generated nondisplaceable binding potential (BPND) and distribution volume ratio (DVR) values using the simplified reference tissue model (SRTM) on the 90-min dynamic PET imaging data, with brain stem and cerebellum as the reference region, respectively. Then, we correlated the standardized uptake value ratio (SUVR)-1 and SUVR averaged from different imaging windows with BPND and DVR, using brain stem and cerebellum as the reference region, respectively. We performed homologous competitive binding assay and autoradiographic saturation binding assay using [18F]SynVesT-1 to calculate the Bmax and Kd.

Results

Using brain stem as the reference region, the averaged SUVR-1 from 30 to 60 min postinjection correlated well with the BPND calculated using SRTM. Using cerebellum as the reference region, the averaged SUVR from 30 to 60 min postinjection correlated well with the SRTM DVR. From the homologous competitive binding assay and autoradiographic saturation binding assay, the calculated the Bmax and Kd were 4.5–18 pmol/mg protein and 9.8–19.6 nM, respectively, for rodent brain tissue.

Conclusions

This simplified SUVR method provides reasonable SV2A measures in APP/PS1 mice and their littermate controls. Our data indicate that, in lieu of a full 90-min dynamic scan, a 30-min static PET scan (from 30 to 60 min postinjection) would be sufficient to provide quantification data on SV2A expression, equivalent to the data generated from kinetic modeling. The methods developed here are readily applicable to the evaluation of therapeutic effects of novel drugs in this rodent model using [18F]SynVesT-1 and small animal PET.

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

Access this article

Log in via an institution

Price includes VAT (Canada)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH (1994) Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci 14:5223–5235

    Article  CAS  Google Scholar 

  2. Cai Z, Li S, Matuskey D, Nabulsi N, Huang Y (2019) PET imaging of synaptic density: A new tool for investigation of neuropsychiatric diseases. Neuroscience Letters 691:44–50

    Article  CAS  Google Scholar 

  3. Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, Nabulsi N, Matuskey D, Angarita GA, Pietrzak RH, Duman RS, Sanacora G, Krystal JH, Carson RE, Esterlis I (2019) Lower synaptic density is associated with depression severity and network alterations. Nat Commun 10:1529

    Article  Google Scholar 

  4. Finnema SJ, Nabulsi NB, Eid T et al (2016) Imaging synaptic density in the living human brain. Sci Transl Med 8:348ra396

    Article  Google Scholar 

  5. Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel MC, Wells L, Creeney H, Bonsall D, Rogdaki M, Shatalina E, Reis Marques T, Rabiner EA, Gunn RN, Natesan S, Vernon AC, Howes OD (2020) Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nat Commun 11:246

    Article  CAS  Google Scholar 

  6. Matuskey D, Tinaz S, Wilcox KC, Naganawa M, Toyonaga T, Dias M, Henry S, Pittman B, Ropchan J, Nabulsi N, Suridjan I, Comley RA, Huang Y, Finnema SJ, Carson RE (2020) Synaptic changes in Parkinson disease assessed with in vivo imaging. Ann Neurol 87:329–338

    Article  CAS  Google Scholar 

  7. Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, Lin SF, Deo A, Price N, Wood M, Lara-Jaime T, Montel F, Laruelle M, Carson RE, Hannestad J, Huang Y (2016) Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. J Nucl Med 57:777–784

    Article  CAS  Google Scholar 

  8. Mecca AP, Chen M-K, O'Dell RS, Naganawa M, Toyonaga T, Godek TA, Harris JE, Bartlett HH, Zhao W, Nabulsi NB, Wyk BCV, Varma P, Arnsten AFT, Huang Y, Carson RE, Dyck CH (2020) In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET. Alzheimer’s & Dementia 16:974–982

    Article  Google Scholar 

  9. Chen M-K, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, Najafzadeh S, Ropchan J, Lu Y, McDonald JW, Michalak HR, Nabulsi NB, Arnsten AFT, Huang Y, Carson RE, van Dyck CH (2018) Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurology 75:1215–1224

    Article  Google Scholar 

  10. Toyonaga T, Smith LM, Finnema SJ, Gallezot JD, Naganawa M, Bini J, Mulnix T, Cai Z, Ropchan J, Huang Y, Strittmatter SM, Carson RE (2019) In vivo synaptic density imaging with 11C-UCB-J detects treatment effects of saracatinib in a mouse model of Alzheimer disease. J Nucl Med 60:1780–1786

    Article  CAS  Google Scholar 

  11. Cai Z, Li S, Zhang W, Pracitto R, Wu X, Baum E, Finnema SJ, Holden D, Toyonaga T, Lin SF, Lindemann M, Shirali A, Labaree DC, Ropchan J, Nabulsi N, Carson RE, Huang Y (2020) Synthesis and preclinical evaluation of an (18)F-labeled synaptic vesicle glycoprotein 2A PET imaging probe: [(18)F]SynVesT-2. ACS Chem Neurosci 11:592–603

    Article  CAS  Google Scholar 

  12. Li S, Cai Z, Wu X, Holden D, Pracitto R, Kapinos M, Gao H, Labaree D, Nabulsi N, Carson RE, Huang Y (2019) Synthesis and in vivo evaluation of a novel PET radiotracer for imaging of synaptic vesicle glycoprotein 2A (SV2A) in nonhuman primates. ACS Chem Neurosci 10:1544–1554

    Article  CAS  Google Scholar 

  13. Naganawa M, Li S, Nabulsi NB, Henry S, Zheng MQ, Pracitto R, Cai Z, Gao H, Kapinos M, Labaree D, Matuskey D, Huang Y, Carson RE (2020) First-in-human evaluation of 18F-SynVesT-1, a novel radioligand for PET imaging of synaptic vesicle protein 2A. J Nucl Med. https://doi.org/10.2967/jnumed.120.249144

  14. Jankowsky JL, Fadale DJ, Anderson J et al (2003) Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase. Human Molecular Genetics 13:159–170

    Article  Google Scholar 

  15. Gimbel DA, Nygaard HB, Coffey EE, Gunther EC, Lauren J, Gimbel ZA, Strittmatter SM (2010) Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J Neurosci 30:6367–6374

    Article  CAS  Google Scholar 

  16. Um JW, Nygaard HB, Heiss JK, Kostylev MA, Stagi M, Vortmeyer A, Wisniewski T, Gunther EC, Strittmatter SM (2012) Alzheimer amyloid-β oligomer bound to post-synaptic prion protein activates Fyn to impair neurons. Nature Neuroscience 15:1227–1235

    Article  CAS  Google Scholar 

  17. Um Ji W, Kaufman Adam C, Kostylev M et al (2013) Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer Aβ oligomer bound to cellular prion protein. Neuron 80:531

    Article  Google Scholar 

  18. Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158

    Article  CAS  Google Scholar 

  19. Logan J, Fowler JS, Volkow ND, Wang GJ, Ding YS, Alexoff DL (1996) Distribution volume ratios without blood sampling from graphical analysis of PET data. J Cereb Blood Flow Metab 16:834–840

    Article  CAS  Google Scholar 

  20. Kaminski RM, Gillard M, Leclercq K, Hanon E, Lorent G, Dassesse D, Matagne A, Klitgaard H (2009) Proepileptic phenotype of SV2A-deficient mice is associated with reduced anticonvulsant efficacy of levetiracetam. Epilepsia 50:1729–1740

    Article  CAS  Google Scholar 

  21. Gillard M, Fuks B, Leclercq K, Matagne A (2011) Binding characteristics of brivaracetam, a selective, high affinity SV2A ligand in rat, mouse and human brain: relationship to anti-convulsant properties. Eur J Pharmacol 664:36–44

    Article  CAS  Google Scholar 

  22. Patel S, Knight A, Krause S et al (2019) Preclinical in vitro and in vivo characterization of synaptic vesicle 2A-Targeting compounds amenable to F-18 labeling as potential pet radioligands for imaging of synapse integrity. Mol Imaging Biol. 22:832–841

    Article  Google Scholar 

  23. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 101:9861–9866

    Article  CAS  Google Scholar 

  24. Mercier J, Archen L, Bollu V, Carré S, Evrard Y, Jnoff E, Kenda B, Lallemand B, Michel P, Montel F, Moureau F, Price N, Quesnel Y, Sauvage X, Valade A, Provins L (2014) Discovery of heterocyclic nonacetamide synaptic vesicle protein 2A (SV2A) ligands with single-digit nanomolar potency: opening avenues towards the first SV2A positron emission tomography (PET) ligands. ChemMedChem 9:693–698

    Article  CAS  Google Scholar 

  25. Estrada S, Lubberink M, Thibblin A, Sprycha M, Buchanan T, Mestdagh N, Kenda B, Mercier J, Provins L, Gillard M, Tytgat D, Antoni G (2016) [11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A. Nucl Med Biol 43:325–332

    Article  CAS  Google Scholar 

  26. Warnock GI, Aerts J, Bahri MA, Bretin F, Lemaire C, Giacomelli F, Mievis F, Mestdagh N, Buchanan T, Valade A, Mercier J, Wood M, Gillard M, Seret A, Luxen A, Salmon E, Plenevaux A (2014) Evaluation of 18F-UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain. J Nucl Med 55:1336–1341

    Article  CAS  Google Scholar 

  27. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, Merry KM, Shi Q, Rosenthal A, Barres BA, Lemere CA, Selkoe DJ, Stevens B (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712–716

    Article  CAS  Google Scholar 

  28. Pozueta J, Lefort R, Shelanski ML (2013) Synaptic changes in Alzheimer’s disease and its models. Neuroscience 251:51–65

    Article  CAS  Google Scholar 

  29. Bertoglio D, Verhaeghe J, Miranda A, et al. (2019) Validation and noninvasive kinetic modeling of [(11)C]UCB-J PET imaging in mice. J Cereb Blood Flow Metab 0:271678X19864081.

  30. Naganawa M, Gallezot J-D, Finnema S, Matuskey D, Mecca AP, Nabulsi NB, Labaree D, Ropchan J, Malison RT, D'Souza DC, Esterlis I, Detyniecki K, van Dyck CH, Huang Y, Carson RE (2020) Simplified quantification of 11C-UCB-J PET evaluated in a large human cohort. J Nucl Med. https://doi.org/10.2967/jnumed.120.243949

  31. Cai Z, Li S, Zhang W et al (2020) Synthesis and preclinical evaluation of an 18F-labeled synaptic vesicle glycoprotein 2A PET imaging probe: [18F]SynVesT-2. ACS Chem Neurosci 11(4):592–603

    Article  CAS  Google Scholar 

  32. Li S, Cai Z, Zhang W, Holden D, Lin SF, Finnema SJ, Shirali A, Ropchan J, Carre S, Mercier J, Carson RE, Nabulsi N, Huang Y (2019) Synthesis and in vivo evaluation of [(18)F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Eur J Nucl Med Mol Imaging 46:1952–1965

    Article  CAS  Google Scholar 

  33. Rossano S, Toyonaga T, Finnema SJ et al (2019) Assessment of a white matter reference region for (11)C-UCB-J PET quantification. J Cereb Blood Flow Metab 40:1890–1901

    Article  Google Scholar 

Download references

Acknowledgments

The authors would like to acknowledge the Yale PET Center staff for their expert technical assistance. The authors thank Ivailo Mihaylov and Anthony D’Abramo Jr for their assistance with autoradiography study.

Funding

This research was supported by National Institutes of Health (NIH) K01EB023312, R01AG058773, R01AG052560. Z.C. is an Archer Foundation Research Scientist.

Author information

Author notes

  1. Pragalath Sadasivam and ** Xu, Ming-Qiang Zheng, Yiyun Huang, Richard E. Carson & Zhengxin Cai

  2. Program in Cellular Neuroscience, Neurodegeneration, and Repair, Departments of Cell Biology, Neurology and Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Joshua Spurrier & Stephen M. Strittmatter

Authors
  1. Pragalath Sadasivam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. **aotian T. Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takuya Toyonaga
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Supum Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu** Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming-Qiang Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Joshua Spurrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yiyun Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stephen M. Strittmatter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Richard E. Carson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhengxin Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhengxin Cai.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with ethical standards of the Yale University Institutional Animal Care and Use Committee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 1193 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sadasivam, P., Fang, X.T., Toyonaga, T. et al. Quantification of SV2A Binding in Rodent Brain Using [18F]SynVesT-1 and PET Imaging. Mol Imaging Biol 23, 372–381 (2021). https://doi.org/10.1007/s11307-020-01567-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-020-01567-9

Key words

Search

Navigation