Novel 18F-Labeled κ-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates

@article{Li2018Novel1,
  title={Novel 18F-Labeled $\kappa$-Opioid Receptor Antagonist as PET Radiotracer: Synthesis and In Vivo Evaluation of 18F-LY2459989 in Nonhuman Primates},
  author={Songye Li and Zhengxin Cai and Ming-Qiang Zheng and Daniel Holden and Mika Naganawa and Shu-Fei Lin and Jim R Ropchan and David C Labaree and Michael Kapinos and Teresa Lara-Jaime and Antonio Navarro and Yiyun Huang},
  journal={The Journal of Nuclear Medicine},
  year={2018},
  volume={59},
  pages={140 - 146}
}
The κ-opioid receptor (KOR) has been implicated in depression, addictions, and other central nervous system disorders and, thus, is an important target for drug development. We previously developed several 11C-labeled PET radiotracers for KOR imaging in humans. Here we report the synthesis and evaluation of 18F-LY2459989 as the first 18F-labeled KOR antagonist radiotracer in nonhuman primates and its comparison with 11C-LY2459989. Methods: The novel radioligand 18F-LY2459989 was synthesized by… 

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References

SHOWING 1-10 OF 40 REFERENCES
An Improved Antagonist Radiotracer for the κ-Opioid Receptor: Synthesis and Characterization of 11C-LY2459989
TLDR
The novel PET radioligand 11C-LY2459989 displayed favorable pharmacokinetic properties, a specific and KOR-selective binding profile, and high specific binding signals in vivo, thus making it a promising PET imaging agent for KOR.
Synthesis and Evaluation of 11C-LY2795050 as a κ-Opioid Receptor Antagonist Radiotracer for PET Imaging
TLDR
This newly developed KOR antagonist tracer has since been advanced to PET imaging of KOR in humans and constitutes the first successful KOR antagonists radiotracer.
Determination of In Vivo Bmax and Kd for 11C-GR103545, an Agonist PET Tracer for κ-Opioid Receptors: A Study in Nonhuman Primates
TLDR
The use of a bolus-plus-infusion protocol with the KOR agonist tracer permitted the successful estimation of Bmax and KdND in vivo, and the mass dose limit in human studies using this novel agonist radiotracer was chosen.
11C-GR103545, a radiotracer for imaging kappa-opioid receptors in vivo with PET: synthesis and evaluation in baboons.
TLDR
11C-GR103545 is a promising PET radiotracer for imaging the kappa-OR and shows excellent brain penetration and uptake kinetics, demonstrating the enantiomeric selectivity of the binding and the advantage of using the pure active enantiomers for PET studies.
Kinetic Modeling of 11C-LY2795050, A Novel Antagonist Radiotracer for PET Imaging of the Kappa Opioid Receptor in Humans
  • M. Naganawa, M. Zheng, Yiyun Huang
  • Biology, Medicine
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2014
TLDR
Binding potentials of 11C-LY2795050 can be determined if the specific binding fraction in the cerebellum is presumed to be unchanged by diseases and experimental conditions.
Test–Retest Reproducibility of Binding Parameters in Humans with 11C-LY2795050, an Antagonist PET Radiotracer for the κ Opioid Receptor
TLDR
The results suggest that quantification of 11C-LY2795050 imaging is reproducible and reliable in regions with moderate and high KOR density and therefore this first antagonist radiotracer is highly useful for PET studies of KOR.
Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors.
TLDR
The synthesis of a first 18F-labeled KOR antagonist radiotracer is reported and the initial PET imaging study in a nonhuman primate is conducted.
[11C]GR103545: novel one-pot radiosynthesis with high specific activity.
...
...