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Research ArticleNeurology

Kinetic Modeling and Test–Retest Reproducibility of 11C-EKAP and 11C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans

Mika Naganawa, Songye Li, Nabeel Nabulsi, Shu-fei Lin, David Labaree, Jim Ropchan, Hong Gao, Michael Mei, Shannan Henry, David Matuskey, Richard E. Carson and Yiyun Huang
Journal of Nuclear Medicine November 2020, 61 (11) 1636-1642; DOI: https://doi.org/10.2967/jnumed.119.227694
Mika Naganawa
Yale PET Center, Yale University, New Haven, Connecticut
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Songye Li
Yale PET Center, Yale University, New Haven, Connecticut
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Nabeel Nabulsi
Yale PET Center, Yale University, New Haven, Connecticut
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Shu-fei Lin
Yale PET Center, Yale University, New Haven, Connecticut
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David Labaree
Yale PET Center, Yale University, New Haven, Connecticut
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Jim Ropchan
Yale PET Center, Yale University, New Haven, Connecticut
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Hong Gao
Yale PET Center, Yale University, New Haven, Connecticut
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Michael Mei
Yale PET Center, Yale University, New Haven, Connecticut
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Shannan Henry
Yale PET Center, Yale University, New Haven, Connecticut
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David Matuskey
Yale PET Center, Yale University, New Haven, Connecticut
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Richard E. Carson
Yale PET Center, Yale University, New Haven, Connecticut
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Yiyun Huang
Yale PET Center, Yale University, New Haven, Connecticut
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Abstract

The κ-opioid receptor (KOR) is implicated in various neuropsychiatric disorders. We previously evaluated an agonist tracer, 11C-GR103545, for PET imaging of KOR in humans. Although 11C-GR103545 showed high brain uptake, good binding specificity, and selectivity for KOR, it displayed slow kinetics and relatively large test–retest variability of total distribution volume (VT) estimates (15%). Therefore, we set out to develop 2 novel KOR agonist radiotracers, 11C-EKAP and 11C-FEKAP. In nonhuman primates, both tracers exhibited faster kinetics than 11C-GR103545 and comparable binding parameters to 11C-GR103545. The aim of this study was to assess their kinetic and binding properties in humans. Methods: Six healthy subjects underwent 120-min test–retest PET scans with both 11C-EKAP and 11C-FEKAP. Metabolite-corrected arterial input functions were measured. Regional time–activity curves were generated for 14 regions of interest. One-tissue-compartment and 2-tissue-compartment (2TC) models and the multilinear analysis-1 (MA1) method were applied to the regional time–activity curves to calculate VT. The time stability of VT and test–retest reproducibility were evaluated. Levels of specific binding, as measured by the nondisplaceable binding potential (BPND) for the 3 tracers (11C-EKAP, 11C-FEKAP, and 11C-GR103545), were compared using a graphical method. Results: For both tracers, regional time–activity curves were fitted well with the 2TC model and MA1 method (t* = 20 min) but not with the 1-tissue-compartment model. Given the unreliably estimated parameters in several fits with the 2TC model and a good VT match between MA1 and 2TC, MA1 was chosen as the appropriate model for both tracers. Mean MA1 VT was highest for 11C-GR103545, followed by 11C-EKAP and then 11C-FEKAP. The minimum scan time for stable VT measurement was 90 and 110 min for 11C-EKAP and 11C-FEKAP, respectively, compared with 140 min for 11C-GR103545. The mean absolute test–retest variability in MA1 VT estimates was 7% and 18% for 11C-EKAP and 11C-FEKAP, respectively. BPND levels were similar for 11C-FEKAP and 11C-GR103545 but were about 25% lower for 11C-EKAP. Conclusion: The 2 novel KOR agonist tracers showed faster tissue kinetics than 11C-GR103545. Even with a slightly lower BPND, 11C-EKAP is judged to be a better tracer for imaging and quantification of KOR in humans, on the basis of the shorter minimum scan time and the excellent test–retest reproducibility of regional VT.

  • PET
  • kinetic modeling
  • receptor imaging
  • brain imaging
  • κ-opioid receptors

Footnotes

  • Published online Mar. 13, 2020.

  • © 2020 by the Society of Nuclear Medicine and Molecular Imaging.
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Journal of Nuclear Medicine: 61 (11)
Journal of Nuclear Medicine
Vol. 61, Issue 11
November 1, 2020
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Kinetic Modeling and Test–Retest Reproducibility of 11C-EKAP and 11C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans
Mika Naganawa, Songye Li, Nabeel Nabulsi, Shu-fei Lin, David Labaree, Jim Ropchan, Hong Gao, Michael Mei, Shannan Henry, David Matuskey, Richard E. Carson, Yiyun Huang
Journal of Nuclear Medicine Nov 2020, 61 (11) 1636-1642; DOI: 10.2967/jnumed.119.227694

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Kinetic Modeling and Test–Retest Reproducibility of 11C-EKAP and 11C-FEKAP, Novel Agonist Radiotracers for PET Imaging of the κ-Opioid Receptor in Humans
Mika Naganawa, Songye Li, Nabeel Nabulsi, Shu-fei Lin, David Labaree, Jim Ropchan, Hong Gao, Michael Mei, Shannan Henry, David Matuskey, Richard E. Carson, Yiyun Huang
Journal of Nuclear Medicine Nov 2020, 61 (11) 1636-1642; DOI: 10.2967/jnumed.119.227694
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Keywords

  • PET
  • Kinetic modeling
  • Receptor imaging
  • brain imaging
  • κ-opioid receptors
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