Molecular Imaging and Biology

, Volume 17, Issue 4, pp 445–449 | Cite as

Molecular Imaging of PDE10A Knockout Mice with a Novel PET Radiotracer: [11C]T-773

  • Miklós Tóth
  • Jenny Häggkvist
  • Vladimir Stepanov
  • Akihiro Takano
  • Ryuji Nakao
  • Nahid Amini
  • Shotaro Miura
  • Haruhide Kimura
  • Takahiko Taniguchi
  • Balázs Gulyás
  • Christer Halldin
Brief Article

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.

Key words

Carbon-11 [11C]T-773 Positron emission tomography (PET) PDE10A CNS Brain imaging Mouse 

References

  1. 1.
    Chappie T, Humphrey J, Menniti F, Schmidt C (2009) PDE10A inhibitors: an assessment of the current CNS drug discovery landscape. Curr Opin Drug Discov Devel 12:458–467PubMedGoogle Scholar
  2. 2.
    Siuciak JA, Chapin DS, Harms JF (2006) Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 51:386–396PubMedCrossRefGoogle Scholar
  3. 3.
    Schmidt CJ, Chapin DS, Cianfrogna J et al (2008) Preclinical characterization of selective phosphodiesterase 10A inhibitors: a new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther 325:681–690PubMedCrossRefGoogle Scholar
  4. 4.
    Tu Z, Xu J, Jones LA et al (2010) Carbon-11 labeled papaverine as a PET tracer for imaging PDE10A: radiosynthesis, in vitro and in vivo evaluation. Nucl Med Biol 37:509–16PubMedCentralPubMedCrossRefGoogle Scholar
  5. 5.
    Plisson C, Salinas C, Weinzimmer D et al (2011) Radiosynthesis and in vivo evaluation of [(11)C]MP-10 as a positron emission tomography radioligand for phosphodiesterase 10A. Nucl Med Biol 38:875–884PubMedCrossRefGoogle Scholar
  6. 6.
    Celen S, Koole M, De Angelis M et al (2010) Preclinical evaluation of 18F-JNJ41510417 as a radioligand for PET imaging of phosphodiesterase-10A in the brain. J Nucl Med 51:1584–91PubMedCrossRefGoogle Scholar
  7. 7.
    Van Laere K, Ahmad RU, Hudyana H et al (2013) Quantification of 18F-JNJ-42259152, a novel phosphodiesterase 10A PET tracer: kinetic modeling and test-retest study in human brain. J Nucl Med 54:1285–1293PubMedCrossRefGoogle Scholar
  8. 8.
    Barret O, Thomae D, Alagille D et al (2012) First in vivo assessment of two PDE10 tracers [18F]MNI654 and [18F]MNI659. J Nucl Med 53(Supplement 1)Google Scholar
  9. 9.
    Barret O, Thomae D, Tavares A et al (2014) In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654. J Nucl Med 55:1297–1304PubMedCrossRefGoogle Scholar
  10. 10.
    Fan J, Zhang X, Li J, Jin H et al (2014) Radiosyntheses and in vivo evaluation of carbon-11 PET tracers for PDE10A in the brain of rodent and nonhuman primate. Bioorg Med Chem 22:2648–2654PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Harada A, Suzuki K, Miura S et al (2014) Characterization of the binding properties of T-773 as a PET radioligand for phosphodiesterase 10A. Nucl Med Biol. doi:10.1016/j.nucmedbio.2014.09.005 PubMedGoogle Scholar
  12. 12.
    Szanda I, Mackewn J, Patay G et al (2011) National electrical manufacturers association NU-4 performance evaluation of the PET component of the NanoPET/CT preclinical PET/CT scanner. J Nucl Med 52:1741–1747PubMedCrossRefGoogle Scholar
  13. 13.
    Nagy K, Tóth M, Major P et al (2013) Performance evaluation of the small-animal nanoScan PET/MRI system. J Nucl Med 54:1825–1832PubMedCrossRefGoogle Scholar
  14. 14.
    Siuciak JA, McCarthy SA, Chapin DS et al (2006) Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. Neuropharmacology 51:374–85PubMedCrossRefGoogle Scholar
  15. 15.
    Stepanov V, Miura S, Takano A et al (2013) Development of a series of novel carbon-11 labeled PDE10A inhibitors. J Labelled Comp Radiopharm 56:S1–S492CrossRefGoogle Scholar
  16. 16.
    Lammertsma AA, Hume SP (1996) Simplified reference tissue model for PET receptor studies. Neuroimage 4:153–158PubMedCrossRefGoogle Scholar
  17. 17.
    Seeger TF, Bartlett B, Coskran TM et al (2003) Immunohistochemical localization of PDE10A in the rat brain. Brain Res 985:113–126PubMedCrossRefGoogle Scholar
  18. 18.
    Celen S, Koole M, Ooms M et al (2013) Preclinical evaluation of [(18)F]JNJ42259152 as a PET tracer for PDE10A. Neuroimage 82:13–22PubMedCrossRefGoogle Scholar

Copyright information

© World Molecular Imaging Society 2015

Authors and Affiliations

  • Miklós Tóth
    • 1
  • Jenny Häggkvist
    • 1
  • Vladimir Stepanov
    • 1
  • Akihiro Takano
    • 1
  • Ryuji Nakao
    • 1
  • Nahid Amini
    • 1
  • Shotaro Miura
    • 1
    • 2
  • Haruhide Kimura
    • 2
  • Takahiko Taniguchi
    • 2
  • Balázs Gulyás
    • 1
    • 3
  • Christer Halldin
    • 1
    • 3
  1. 1.Center for Psychiatric Research, Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
  2. 2.CNS Drug Discovery Unit, Pharmaceutical Research DivisionTAKEDA Pharmaceutical Company, Ltd.FujisawaJapan
  3. 3.Lee Kong Chian School of Medicine, NTU–Imperial CollegeNanyang Technological UniversitySingaporeSingapore

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