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In vivo assessment of [11C]MRB as a prospective PET ligand for imaging the norepinephrine transporter

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Abstract

Purpose

Antagonism of norepinephrine reuptake is now an important pharmacological strategy in the treatment of anxiety and depressive disorders, and many antidepressants have substantial potential occupancy of the norepinephrine transporter (NET) at recommended dosages. Despite the importance of understanding this transporter’s role in psychiatric disease and treatment, a suitable radioligand for studying NET has been slow to emerge. (S,S)-Methylreboxetine (MRB) is among the more promising ligands recently adapted for positron emission tomography (PET), and the present study aimed to evaluate its potential for use in higher primates.

Methods

Affinities for various brain targets were determined in vitro. PET studies were conducted in baboon under both test–retest and blocking conditions using 1 mg/kg nisoxetine.

Results

MRB has sixfold higher affinity for NET than the serotonin transporter, and negligible affinity for other sites. PET studies in baboons showed little regional heterogeneity in binding and were minimally affected by pretreatment with the NET antagonist nisoxetine.

Conclusion

Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [11C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.

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Acknowledgements

The authors thank Holly Brandenburg and Mali Pratap for their assistance with PET studies, and the NIMH-PDSP for ligand assay services. This work was supported by PHS grant MH062185.

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Authors and Affiliations

  1. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Matthew S. Milak, J. S. Dileep Kumar, Jaya Prabhakaran, Vattoly J. Majo, Victoria Arango, J. John Mann & Ramin V. Parsey

  2. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA

    Norman R. Simpson, Ronald L. Van Heertum & J. John Mann

  3. Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA

    Alin J. Severance, Matthew S. Milak, J. S. Dileep Kumar, Victoria Arango, J. John Mann & Ramin V. Parsey

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  1. Alin J. Severance
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  2. Matthew S. Milak
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  3. J. S. Dileep Kumar
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  4. Jaya Prabhakaran
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  5. Vattoly J. Majo
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  6. Norman R. Simpson
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  7. Ronald L. Van Heertum
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  8. Victoria Arango
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  9. J. John Mann
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  10. Ramin V. Parsey
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Correspondence to Ramin V. Parsey.

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Severance, A.J., Milak, M.S., Kumar, J.S.D. et al. In vivo assessment of [11C]MRB as a prospective PET ligand for imaging the norepinephrine transporter. Eur J Nucl Med Mol Imaging 34, 688–693 (2007). https://doi.org/10.1007/s00259-006-0312-2

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  • DOI: https://doi.org/10.1007/s00259-006-0312-2

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