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Molecular Imaging and Biology

, Volume 21, Issue 3, pp 509–518 | Cite as

Development and In Vivo Preclinical Imaging of Fluorine-18-Labeled Synaptic Vesicle Protein 2A (SV2A) PET Tracers

  • Cristian C. ConstantinescuEmail author
  • Cedric Tresse
  • MingQiang Zheng
  • Alexandra Gouasmat
  • Vincent M Carroll
  • Laetitia Mistico
  • David Alagille
  • Christine M. Sandiego
  • Caroline Papin
  • Kenneth Marek
  • John P. Seibyl
  • Gilles D. Tamagnan
  • Olivier Barret
Research Article

Abstract

Purpose

Synaptic vesicle protein 2A (SV2A) serves as a biomarker of synaptic density and positron emission tomography (PET) imaging of SV2A could provide a tool to assess progression of neurodegenerative diseases. Two tracers have primarily been reported and characterized in vivo: [11C]UCB-J and [18F]UCB-H. In early human studies, [11C]UCB-J showed promising results, while its F-18-labeled analogue [18F]UCB-H showed suboptimal specific signal in comparison to [11C]UCB-J. Considering the limited use of [11C]UCB-J to facilities with a cyclotron, having a F-18 variant would facilitate large, multicenter imaging trials. We have screened several F-18 derivatives of UCB-J in non-human primates and identified a promising F-18 PET candidate, [18F]MNI-1126, with additional investigations of the racemate [18F]MNI-1038, affording a signal comparable to [11C]UCB-J.

Procedures

F-18 derivatives of UCB-J and UCB-H were synthesized and administered to non-human primates for microPET imaging. Following screenings, [18F]MNI-1038 (racemate) and [18F]MNI-1126 (R-enantiomer) were identified with the highest signal and favorable kinetics and were selected for further imaging. Kinetic modeling with one- and two-tissue compartmental models, and linear methods were applied to PET data using metabolite-corrected arterial input function. Pre-block scans with levetiracetam (LEV, 10, 30 mg/kg, iv) were performed to determine the tracers’ in vivo specificity for SV2A. Two whole-body PET studies were performed with [18F]MNI-1038 in one male and one female rhesus, and radiation absorbed dose estimates and effective dose (ED, ICRP-103) were estimated with OLINDA/EXM 2.0.

Results

All compounds screened displayed very good brain penetration, with a plasma-free fraction of ~ 40 %. [18F]MNI-1126 and [18F]MNI-1038 showed uptake and distribution the most consistent with UCB-J, while the other derivatives showed suboptimal results, with similar or lower uptake than [18F]UCB-H. VT of [18F]MNI-1126 and [18F]MNI-1038 was high in all gray matter regions (within animal averages ~ 30 ml/cm3) and highly correlated with [11C]UCB-J (r > 0.99). Pre-blocking of [18F]MNI-1126 or [18F]MNI-1038 with LEV showed robust occupancy across all gray matter regions, similar to that reported with [11C]UCB-J (~ 85 % at 30 mg/kg, ~ 65 % at 10 mg/kg). Using the centrum semiovale as a reference region, BPND of [18F]MNI-1126 reached values of up to ~ 30 to 40 % higher than those reported for [11C]UCB-J. From whole-body imaging average ED of [18F]MNI-1038 was estimated to be 22.3 μSv/MBq, with tracer being eliminated via both urinary and hepatobiliary pathways.

Conclusions

We have identified a F-18-labeled tracer ([18F]MNI-1126) that exhibits comparable in vivo characteristics and specificity for SV2A to [11C]UCB-J in non-human primates, which makes [18F]MNI-1126 a promising PET radiotracer for imaging SV2A in human trials.

Key words

SV2A F-18 PET imaging Synaptic density Neurodegenerative disorders MNI-126 

Notes

Compliance with Ethical Standards

This study followed protocols approved by the Yale University Institutional Animal Care and Use Committee.

Conflict of Interest

Keneth Marek and John Seibyl are Invicro equity holders. Kenneth Marek is a scientific consultant for GE Healthcare, Takeda Pharmaceuticals, Denali Therapeutics, Roche Pharma, Prothena Corp., and Lundbeck. All other authors declare that they have no conflict of interest.

Supplementary material

11307_2018_1260_MOESM1_ESM.pdf (1 mb)
ESM 1 (PDF 1043 kb)

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Copyright information

© World Molecular Imaging Society 2018

Authors and Affiliations

  • Cristian C. Constantinescu
    • 1
    Email author
  • Cedric Tresse
    • 1
  • MingQiang Zheng
    • 1
  • Alexandra Gouasmat
    • 1
  • Vincent M Carroll
    • 1
  • Laetitia Mistico
    • 1
  • David Alagille
    • 1
  • Christine M. Sandiego
    • 1
  • Caroline Papin
    • 1
  • Kenneth Marek
    • 1
  • John P. Seibyl
    • 1
  • Gilles D. Tamagnan
    • 1
    • 2
  • Olivier Barret
    • 1
  1. 1.Invicro, LLCNew HavenUSA
  2. 2.Xing ImagingNew HavenUSA

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