Skip to main content

Advertisement

Log in

Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A)

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

Abstract

Purpose

Synaptic abnormalities have been implicated in a variety of neuropsychiatric disorders, including epilepsy, Alzheimer’s disease, and schizophrenia. Hence, PET imaging of the synaptic vesicle glycoprotein 2A (SV2A) may be a valuable in vivo biomarker for neurologic and psychiatric diseases. We previously developed [11C]UCB-J, a PET radiotracer with high affinity and selectivity toward SV2A; however, the short radioactive half-life (20 min for 11C) places some limitations on its broader application. Herein, we report the first synthesis of the longer-lived 18F-labeled counterpart (half-life: 110 min), [18F]UCB-J, and its evaluation in nonhuman primates.

Methods

[18F]UCB-J was synthesized from the iodonium precursors. PET imaging experiments with [18F]UCB-J were conducted in rhesus monkeys to assess the pharmacokinetic and in vivo binding properties. Arterial samples were taken for analysis of radioactive metabolites and generation of input functions. Regional time–activity curves were analyzed using the one-tissue compartment model to derive regional distribution volumes and binding potentials for comparison with [11C]UCB-J.

Results

[18F]UCB-J was prepared in high radiochemical and enantiomeric purity, but low radiochemical yield. Evaluation in nonhuman primates indicated that the radiotracer displayed pharmacokinetic and imaging characteristics similar to those of [11C]UCB-J, with moderate metabolism rate, high brain uptake, fast and reversible binding kinetics, and high specific binding signals.

Conclusion

We have accomplished the first synthesis of the novel SV2A radiotracer [18F]UCB-J. [18F]UCB-J is demonstrated to be an excellent imaging agent and may prove to be useful for imaging and quantification of SV2A expression, and synaptic density, in humans.

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
Scheme 1
Scheme 2
Scheme 3
Scheme 4
Fig. 2
Scheme 5
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Loscher W, Gillard M, Sands ZA, Kaminski RM, Klitgaard H. Synaptic vesicle glycoprotein 2A ligands in the treatment of epilepsy and beyond. CNS Drugs. 2016;30:1055–77. https://doi.org/10.1007/s40263-016-0384-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Bajjalieh SM, Peterson K, Shinghal R, Scheller RH. SV2, a brain synaptic vesicle protein homologous to bacterial transporters. Science. 1992;257:1271–3. https://doi.org/10.1126/science.1519064.

    Article  CAS  PubMed  Google Scholar 

  3. Crowder KM, Gunther JM, Jones TA, Hale BD, Zhang HZ, Peterson MR, et al. Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad Sci U S A. 1999;96:15268–73. https://doi.org/10.1073/pnas.96.26.15268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Mendoza-Torreblanca JG, Vanoye-Carlo A, Phillips-Farfan BV, Carmona-Aparicio L, Gomez-Lira G. Synaptic vesicle protein 2A: basic facts and role in synaptic function. Eur J Neurosci. 2013;38:3529–39. https://doi.org/10.1111/ejn.12360.

    Article  PubMed  Google Scholar 

  5. Feng G, Xiao F, Lu Y, Huang Z, Yuan J, Xiao Z, et al. Down-regulation synaptic vesicle protein 2A in the anterior temporal neocortex of patients with intractable epilepsy. J Mol Neurosci. 2009;39:354–9. https://doi.org/10.1007/s12031-009-9288-2.

    Article  CAS  PubMed  Google Scholar 

  6. Tokudome K, Okumura T, Shimizu S, Mashimo T, Takizawa A, Serikawa T, et al. Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. Sci Rep. 2016;6:27420. https://doi.org/10.1038/srep27420.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, et al. Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2012;109:E2895.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Stockburger C, Miano D, Baeumlisberger M, Pallas T, Arrey TN, Karas M, et al. A mitochondrial role of SV2a protein in aging and Alzheimer’s disease: studies with Levetiracetam. J Alzheimers Dis. 2016;50:201–15. https://doi.org/10.3233/JAD-150687.

    Article  CAS  PubMed  Google Scholar 

  9. Hou Z, Lei H, Hong S, Sun B, Fang K, Lin X, et al. Functional changes in the frontal cortex in Parkinson’s disease using a rat model. J Clin Neurosci. 2010;17:628–33. https://doi.org/10.1016/j.jocn.2009.07.101.

    Article  CAS  PubMed  Google Scholar 

  10. Mattheisen M, Muhleisen TW, Strohmaier J, Treutlein J, Nenadic I, Alblas M, et al. Genetic variation at the synaptic vesicle gene SV2A is associated with schizophrenia. Schizophr Res. 2012;141:262–5. https://doi.org/10.1016/j.schres.2012.08.027.

    Article  PubMed  Google Scholar 

  11. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–91. https://doi.org/10.1126/science.1074069.

    Article  CAS  PubMed  Google Scholar 

  12. Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement. 2011;7:280–92. https://doi.org/10.1016/j.jalz.2011.03.003.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Estrada S, Lubberink M, Thibblin A, Sprycha M, Buchanan T, Mestdagh N, et al. [11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2A. Nucl Med Biol. 2016;43:325–32. https://doi.org/10.1016/j.nucmedbio.2016.03.004.

    Article  CAS  PubMed  Google Scholar 

  14. Warnock GI, Aerts J, Bahri MA, Bretin F, Lemaire C, Giacomelli F, et al. Evaluation of 18F-UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain. J Nucl Med. 2014;55:1336–41. https://doi.org/10.2967/jnumed.113.136143.

    Article  CAS  PubMed  Google Scholar 

  15. Becker G, Warnier C, Serrano ME, Bahri MA, Mercier J, Lemaire C, et al. Pharmacokinetic characterization of [18F]UCB-H PET radiopharmaceutical in the rat brain. Mol Pharm. 2017;14:2719–25. https://doi.org/10.1021/acs.molpharmaceut.7b00235.

    Article  CAS  PubMed  Google Scholar 

  16. Bretin F, Bahri MA, Bernard C, Warnock G, Aerts J, Mestdagh N, et al. Biodistribution and radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H: first-in-human study. Mol Imaging Biol. 2015;17:557–64. https://doi.org/10.1007/s11307-014-0820-6.

    Article  CAS  PubMed  Google Scholar 

  17. Bahri MA, Plenevaux A, Aerts J, Bastin C, Becker G, Mercier J, et al. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [18F]UCB-H. Alzheimers Dement (NY). 2017;3:481–6. https://doi.org/10.1016/j.trci.2017.08.004.

    Article  Google Scholar 

  18. Mercier J, Archen L, Bollu V, Carre S, Evrard Y, Jnoff E, et al. 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. 2014;9:693–8. https://doi.org/10.1002/cmdc.201300482.

    Article  CAS  PubMed  Google Scholar 

  19. Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. 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. 2016;57:777–84. https://doi.org/10.2967/jnumed.115.168179.

    Article  CAS  PubMed  Google Scholar 

  20. Finnema SJ, Nabulsi NB, Mercier J, Lin SF, Chen MK, Matuskey D, et al. Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. J Cereb Blood Flow Metab. 2017:271678X17724947. doi:https://doi.org/10.1177/0271678X17724947.

  21. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra96. https://doi.org/10.1126/scitranslmed.aaf6667.

    Article  CAS  PubMed  Google Scholar 

  22. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352:712–6. https://doi.org/10.1126/science.aad8373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. van Spronsen M, Hoogenraad CC. Synapse pathology in psychiatric and neurologic disease. Curr Neurol Neurosci Rep. 2010;10:207–14. https://doi.org/10.1007/s11910-010-0104-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kaufman AC, Salazar SV, Haas LT, Yang J, Kostylev MA, Jeng AT, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol. 2015;77:953–71. https://doi.org/10.1002/ana.24394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Haas LT, Salazar SV, Smith LM, Zhao HR, Cox TO, Herber CS, et al. Silent allosteric modulation of mGluR5 maintains glutamate signaling while rescuing Alzheimer’s mouse phenotypes. Cell Rep. 2017;20:76–88. https://doi.org/10.1016/j.celrep.2017.06.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hilton J, Yokoi F, Dannals RF, Ravert HT, Szabo Z, Wong DF. Column-switching HPLC for the analysis of plasma in PET imaging studies. Nucl Med Biol. 2000;27:627–30.

    Article  CAS  PubMed  Google Scholar 

  27. Chen MK, Mecca AP, Naganawa M, Finnema SJ, Toyonaga T, Lin SF, et al. Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75:1215–24. https://doi.org/10.1001/jamaneurol.2018.1836.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sandiego CM, Weinzimmer D, Carson RE. Optimization of PET-MR registrations for nonhuman primates using mutual information measures: a multi-transform method (MTM). Neuroimage. 2013;64:571–81. https://doi.org/10.1016/j.neuroimage.2012.08.051.

    Article  PubMed  Google Scholar 

  29. Gunn RN, Gunn SR, Cunningham VJ. Positron emission tomography compartmental models. J Cereb Blood Flow Metab. 2001;21:635–52. https://doi.org/10.1097/00004647-200106000-00002.

    Article  CAS  PubMed  Google Scholar 

  30. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, et al. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–9. https://doi.org/10.1038/sj.jcbfm.9600493.

    Article  CAS  PubMed  Google Scholar 

  31. Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50. https://doi.org/10.1038/jcbfm.2009.190.

    Article  PubMed  Google Scholar 

  32. Pike VW, Aigbirhio FI. Reactions of cyclotron-produced [18F]fluoride with diaryliodonium salts-a novel single-step route to no-carrier-added [18]fluoroarenes. J Chem Soc Chem Commun. 1995:2215–6. https://doi.org/10.1039/C39950002215.

  33. Rotstein BH, Stephenson NA, Vasdev N, Liang SH. Spirocyclic hypervalent iodine(III)-mediated radiofluorination of non-activated and hindered aromatics. Nat Commun. 2014;5:4365. https://doi.org/10.1038/ncomms5365.

    Article  CAS  PubMed  Google Scholar 

  34. Cardinale J, Ermert J, Humpert S, Coenen HH. Iodonium ylides for one-step, no-carrier-added radiofluorination of electron rich arenes, exemplified with 4-(([F-18] fluorophenoxy)-phenylmethyl) piperidine NET and SERT ligands. RSC Adv. 2014;4:17293–9. https://doi.org/10.1039/c4ra00674g.

    Article  CAS  Google Scholar 

  35. Jin XD, Davies RP. Copper-catalysed aromatic-Finkelstein reactions with amine-based ligand systems. Catal Sci Technol. 2017;7:2110–7. https://doi.org/10.1039/c7cy00538e.

    Article  CAS  Google Scholar 

  36. Bielawski M, Malmgren J, Pardo LM, Wikmark Y, Olofsson B. One-pot synthesis and applications of N-heteroaryl iodonium salts. Chemistryopen. 2014;3:19–22. https://doi.org/10.1002/open.201300042.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Neumann CN, Hooker JM, Ritter T. Concerted nucleophilic aromatic substitution with 19F and 18F. Nature. 2016;538:274. https://doi.org/10.1038/nature19311.

    Article  CAS  PubMed  Google Scholar 

  38. Makaravage KJ, Brooks AF, Mossine AV, Sanford MS, Scott PJ. Copper-mediated Radiofluorination of Arylstannanes with [18F]KF. Org Lett. 2016. https://doi.org/10.1021/acs.orglett.6b02911.

  39. Sanford MS, Scott PJ. Moving metal-mediated 18F-fluorination from concept to clinic. ACS Cent Sci. 2016;2:128–30. https://doi.org/10.1021/acscentsci.6b00061.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sander K, Gendron T, Yiannaki E, Cybulska K, Kalber TL, Lythgoe MF, et al. Sulfonium salts as leaving groups for aromatic labelling of drug-like small molecules with fluorine-18. Sci Rep. 2015;5:9941. https://doi.org/10.1038/srep09941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tredwell M, Preshlock SM, Taylor NJ, Gruber S, Huiban M, Passchier J, et al. A general copper-mediated nucleophilic 18F fluorination of arenes. Angew Chem Int Ed Engl. 2014;53:7751–5. https://doi.org/10.1002/anie.201404436.

    Article  CAS  PubMed  Google Scholar 

  42. Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. P Natl Acad Sci USA. 2004;101:9861–6. https://doi.org/10.1073/pnas.0308208101.

    Article  CAS  Google Scholar 

  43. Laruelle M, Slifstein M, Huang Y. Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography. Mol Imaging Biol. 2003;5:363–75.

    Article  PubMed  Google Scholar 

  44. Cai Z, Li S, Matuskey D, Nabulsi N, Huang Y. PET imaging of synaptic density: a new tool for investigation of neuropsychiatric diseases. Neurosci Lett. 2019;691:44–50. https://doi.org/10.1016/j.neulet.2018.07.038.

    Article  CAS  PubMed  Google Scholar 

  45. Li S, Cai Z, Wu X, Holden D, Pracitto R, Kapinos M, et al. Synthesis and in vivo evaluation of a novel PET radiotracer for imaging of synaptic vesicle glycoprotein 2A (SV2A) in nonhuman Primates. ACS Chem Neurosci. 2019;10:1544–54. https://doi.org/10.1021/acschemneuro.8b00526.

    Article  CAS  PubMed  Google Scholar 

  46. Constantinescu CC, Tresse C, Zheng M, Gouasmat A, Carroll VM, Mistico L, et al. Development and in vivo preclinical imaging of Fluorine-18-labeled synaptic vesicle protein 2A (SV2A) PET tracers. Mol Imaging Biol. 2018. https://doi.org/10.1007/s11307-018-1260-5.

Download references

Acknowledgements

The authors thank the staff at the Yale PET Center for their expert assistance in this work. Z.C. was supported by the NIH/NIBIB under award number K01 EB023312.

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Songye Li or 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 the 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.

This article is part of the Topical Collection on Translational Research

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, S., Cai, Z., Zhang, W. et al. Synthesis and in vivo evaluation of [18F]UCB-J for PET imaging of synaptic vesicle glycoprotein 2A (SV2A). Eur J Nucl Med Mol Imaging 46, 1952–1965 (2019). https://doi.org/10.1007/s00259-019-04357-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-04357-w

Keywords

Navigation