Abstract
Purpose
[11C]T-773 is a new radioligand for positron emission tomography (PET) targeting the phosphodiesterase 10A enzyme (PDE10A). PDE10A is highly expressed in the striatum by medium spiny neurons, and it has been demonstrated to be involved in the regulation of striatal signaling through the reduction of medium spiny neuronal sensitivity towards glutamatergic excitation. PDE10A is associated with Parkinson’s disease and different neuropsychiatric disorders such as Huntington’s disease, obsessive-compulsive disorders (OCD) and schizophrenia. Studies have indicated that the inhibition of PDE10A may represent a novel therapeutic approach to the treatment of the aforementioned diseases characterized by the reduced activity of medium spiny neurons. An appropriate PET radioligand for PDE10A would help to facilitate drug development and drug evaluation.
Procedures
We have evaluated the [11C]T-773 ligand in PDE10A knockout mice (heterozygous [HET] and homozygous [HOM]) as well as in normal control animals (WILD) with PET.
Results
The regional percent standardized uptake values (%SUV; mean ± SD) in the striatum were 48.2 ± 1.0 (HOM), 63.6 ± 5.3 (HET) and 85.1 ± 6.3 (WILD). Between each animal group the striatal %SUV values were significantly different (p < 0.0001). The striatal BPND values (mean ± SD) were 0.0 ± 0.0 (HOM), 0.14 ± 0.07 (HET) and 0.56 ± 0.15 (WILD). The BPND values were significantly lower in homozygous and heterozygous animals compared to wild type (p < 0.0001).
Conclusions
The novel PDE10A radioligand [11C]T-773 shows increased signals with higher levels of PDE10A and acceptable binding in the striatum in control animals compared to knockout mice.
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Acknowledgments
This work was sponsored by the Takeda Pharmaceutical Company Limited. The authors express their gratitude to members of the Karolinska PET group for their contribution to the experiments. Special thanks to Björn Wolbert, Kálmán Nagy and Sara Lundqvist for their participation in the PET imaging. The research leading to these results has received funding from the COST Action TD1007 (“Bimodal PET-MRI molecular imaging technologies and applications for in vivo monitoring of disease and biological processes”).
Conflicts of Interest
This work was sponsored by Takeda Pharmaceutical Company Limited. Shotaro Miura, Haruhide Kimura and Takahiko Taniguchi were employees of Takeda Pharmaceutical Company Limited when the study was conducted.
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Tóth, M., Häggkvist, J., Stepanov, V. et al. Molecular Imaging of PDE10A Knockout Mice with a Novel PET Radiotracer: [11C]T-773. Mol Imaging Biol 17, 445–449 (2015). https://doi.org/10.1007/s11307-015-0822-z
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DOI: https://doi.org/10.1007/s11307-015-0822-z