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Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [18F]UCB-H: First-in-Human Study

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Abstract

Purpose

[18F]UCB-H is a novel radiotracer with a high affinity for synaptic vesicle glycoprotein 2A (SV2A), a protein expressed in synaptic vesicles. SV2A is the binding site of levetiracetam, a “first-in-class” antiepileptic drug with a distinct but still poorly understood mechanism of action. The objective of this study was to determine the biodistribution and radiation dosimetry of [18F]UCB-H in a human clinical trial and to establish injection limits according to biomedical research guidelines. Additionally, the clinical radiation dosimetry results were compared to estimations in previously published preclinical data.

Procedures

Dynamic whole body positron emission tomography/X-ray computed tomography (PET/CT) imaging was performed over approximately 110 min on five healthy male volunteers after injection of 144.5 ± 7.1 MBq (range, 139.1–156.5 MBq) of [18F]UCB-H. Major organs were delineated on CT images, and time–activity curves were obtained from co-registered dynamic PET emission scans. The bladder could only be delineated on PET images. Time-integrated activity coefficients were calculated as area under the curve using trapezoidal numerical integration. Urinary excretion data based on PET activities including voiding was also simulated using the dynamic bladder module of OLINDA/EXM. The radiation dosimetry was calculated using OLINDA/EXM.

Results

The effective dose to the OLINDA/EXM 70-kg standard male was 1.54 × 10−2 ± 6.84 × 10−4 millisieverts (mSv)/MBq, with urinary bladder wall, gallbladder wall, and the liver receiving the highest absorbed dose. The brain, the tracer’s main organ of interest, received an absorbed dose of 1.89 × 10−2 ± 2.32 × 10−3 mGy/MBq.

Conclusions

This first human dosimetry study of [18F]UCB-H indicated that the tracer shows similar radiation burdens to widely used common clinical tracers. Single injections of at maximum 672 MBq for US practice and 649 MBq for European practice keep radiation exposure below recommended limits. Recently published preclinical dosimetry data extrapolated from mice provided satisfactory prediction of total body and effective dose but showed significant differences in organ absorbed doses compared to human data.

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References

  1. Jahn R, Fasshauer D (2012) Molecular machines governing exocytosis of synaptic vesicles. Nature 490:201–207

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Janz R, Südhof TC, Hammer RE et al (1999) Essential roles in synaptic plasticity for synaptogyrin I and synaptophysin I. Neuron 24:687–700

    Article  CAS  PubMed  Google Scholar 

  3. Crevecoer J, Kaminski RM, Rogister B et al (2014) Expression pattern of synaptic vesicle protein 2 (SV2) isoforms in patients with temporal lobe epilepsy and hippocamal sclerosis. Neuropathol Appl Neurobiol 40:191–204

    Article  Google Scholar 

  4. Nowack A, Yao J, Custer KL, Bajjalieh SM (2010) SV2 regulates neurotransmitter release via multiple mechanisms. Am J Physiol Cell Physiol 299:C960–C967

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Bajjalieh SM, Frantz GD, Weimann JM et al (1994) Differential expression of synaptic vesicle protein 2 (SV2). J Neurosci 14:5223–5235

    CAS  PubMed  Google Scholar 

  6. Janz R, Sudhof TC (1999) SV2C is a synaptic vesicle protein with an unusually restricted localization: anatomy of a synaptic vesicle protein family. Neuroscience 94:1279–1290

    Article  CAS  PubMed  Google Scholar 

  7. Janz R, Goda Y, Geppert M, Missler M, Sudhof TC (1999) SV2A and SV2B function as redundant CA2+ regulators in neurotransmitter release. Neuron 24:1003–1016

    Article  CAS  PubMed  Google Scholar 

  8. Lynch BA, Lambeng N, Nocka K et al (2004) The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A 101:9861–9866

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Bakker A, Krauss GL, Albert MS et al (2012) Reduction of hippocampal hyperactivity improves cognition in amnestic mild cognitive impairment. Neuron 74:467–474

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Patsalos PN (2000) Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 85:77–85

    Article  CAS  PubMed  Google Scholar 

  11. Cai H, Mangner TJ, Muzik O et al (2014) Radiosynthesis of 11C-Levetiracetam: a potential marker for PET imaging of SV2A expression. ACS Med Chem Lett 5:1152–1155

    Article  CAS  PubMed  Google Scholar 

  12. Warnock GI, Aerts J, Bahri MA et al (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  PubMed  Google Scholar 

  13. Bretin F, Warnock G, Bahri MA et al (2013) Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H. Eur J Nucl Med Mol Imaging Res 3:35–42

    Google Scholar 

  14. Verbruggen A, Coenen HH, Deverre JR et al (2008) Guideline to regulations for radiopharmaceuticals in early phase clinical trials in the EU. Eur J Nucl Med Mol Imaging 35:2144–2151

    Article  CAS  PubMed  Google Scholar 

  15. Siegel JA, Thomas SR, Stubbs JB, et al. (1999) MIRD pamphlet no. 16: techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates. J Nucl Med 4037S-61S

  16. Surti S, Kuhn A, Werner ME, Perkins AE, Kolthammer J, Karp JS (2007) Performance of Philips Gemini TF PET/CT scanner with special consideration for its time-of-flight imaging capabilities. J Nucl Med 48:471–480

    PubMed  Google Scholar 

  17. Feldkamp LA, Davis LC, Wress JW (1984) Practical cone-beam algorithm. J Opt Soc Am A Opt Image Sci Vis 1:612–619

    Article  Google Scholar 

  18. Wang W, Hu Z, Gualtieri EE et al (2006) Systematic and distributed time-of-flight list mode PET reconstruction [proceeding]. IEEE Nucl Sci Symposium Conference Record 3:1715–1722

    Google Scholar 

  19. Boellaard R, Hristova I, Ettinger S et al (2013) EARL FDG-PET/CT accreditation program: feasibility, overview and results of first 55 successfully accredited sites [abstract]. Soc Nucl Med Ann Meet Abs 54:2052

    Google Scholar 

  20. Eckerman KF, Cristy M, Ryman JC (1996) The ORNL mathematical phantom series. Oak Ridge National Laboratory, Oak Ridge

    Google Scholar 

  21. Stabin MG, Sparks RB, Crowe E (2005) OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 46:1023–1027

    PubMed  Google Scholar 

  22. Stabin MG (2008) Steps in dose calculations. In: Fundamentals of nuclear medicine dosimetry. Springer, pp 77-118

  23. Laymon CM, Narendran R, Mason NS et al (2011) Human biodistribution and dosimetry of the PET radioligand [11C] flumazenil (FMZ). Mol Imag Biol 14:115–122

    Article  Google Scholar 

  24. Bullich S, Slifstein M, Passchier J et al (2011) Biodistribution and radiation dosimetry of the glycine transporter-1 ligand 11C-GSK931145 determined from primate and human whole-body PET. Mol Imag Biol 13:776–784

    Article  Google Scholar 

  25. Mizrahi R, Rusjan PM, Vitcu I et al (2013) Whole body biodistribution and radiation dosimetry in humans of a new PET ligand, [18F]-FEPPA, to image translocator protein (18 kDa). Mol Imag Biol 15:353–359

    Article  Google Scholar 

  26. ICRP (1991) 1990 Recommendations of the international commission on radiological protection. In: ICRP Publication 60. Pergamon, New York

  27. ICRP (2007) ICRP publication 103. Ann ICPR 37:1–332

    Google Scholar 

  28. Eberlein U, Bröer JH, Vandevoorde C et al (2011) Biokinetics and dosimetry of commonly used radiopharmaceuticals in diagnostic nuclear medicine—a review. Eur J Nucl Med Mol Imaging 38:2269–2281

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Deloar HM, Fujiwara T, Shidahara M et al (1998) Estimation of absorbed dose for 2-[F-18] fluoro-2-deoxy-D-glucose using whole-body positron emission tomography and magnetic resonance imaging. Eur J Nucl Med Mol Imaging 25:565–574

    Article  CAS  Google Scholar 

  30. Waxman AD, Herholz K, Lewis DH, et al. (2009) Society of nuclear medicine procedure guideline for FDG PET brain imaging. Soc Nucl Med (Version 1.0)

  31. Code of Federal Regulations (2014) Drugs for human use, title 21, volume 5. Available at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=361.1, FDA

  32. Kirschner AS, Ice RD, Beierwaltes WH (1975) Radiation dosimetry of 131I-19-iodocholesterol: the pitfalls of using tissue concentration data, the author’s reply. J Nucl Med 16:248–249

    CAS  Google Scholar 

  33. McParland BJ (2010) Nuclear medicine radiation dosimetry. In: The biodistribution I—preclinical. Springer, pp 519-532

  34. Fueger BJ, Czernin J, Hildebrandt I et al (2006) Impact of animal handling on the results of 18F-FDG PET studies in mice. J Nucl Med 47:999–1006

    CAS  PubMed  Google Scholar 

  35. Sakata M, Oda K, Toyohara J et al (2013) Direct comparison of radiation dosimetry of six PET tracers using human whole-body imaging and murine biodistribution studies. Ann Nucl Med 27:285–296

    Article  CAS  PubMed  Google Scholar 

  36. Zanotti-Fregonara P, Innis RB (2012) Suggested pathway to assess the radiation safety of 11C-labeled tracers for first-in-human studies. Eur J Nucl Med Mol Imaging 39:544–547

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

This work was funded by the Walloon Region Public Private Partnership NEUROCOM, with the University of Liège and UCB Pharma as partners. F. Bretin is supported by Marie Curie Initial Training Network (MCITN) “Methods in Neuroimaging” under Grant No. #MC-ITN-238593. M.A. Bahri is a “collaborateur logistique” and A. Plenevaux is a senior research associate from FRS-FNRS Belgium. We also acknowledge the comments of the reviewers, which helped to improve the contents of this article.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Correspondence to E. Salmon.

Additional information

A. Plenevaux and E. Salmon contributed equally to this work.

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Bretin, F., Bahri, M.A., Bernard, C. et al. Biodistribution and Radiation Dosimetry for the Novel SV2A Radiotracer [18F]UCB-H: First-in-Human Study. Mol Imaging Biol 17, 557–564 (2015). https://doi.org/10.1007/s11307-014-0820-6

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