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


CONCLUSIONS
Despite improvement over previous ligands for imaging NET in vivo, the low signal to noise ratio indicates [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.
Severance
Alin J
AJ
Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA.
Milak
Matthew S
MS
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.|Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA.
Kumar
J S Dileep
JSD
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.|Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA.
Prabhakaran
Jaya
J
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Majo
Vattoly J
VJ
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Simpson
Norman R
NR
Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Van Heertum
Ronald L
RL
Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
Arango
Victoria
V
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.|Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA.
Mann
J John
JJ
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA.|Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA.|Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA.
Parsey
Ramin V
RV
Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. rparsey@neuron.cpmc.columbia.edu.|Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA. rparsey@neuron.cpmc.columbia.edu.
D018759:Adrenergic Uptake Inhibitors; D000818:Animals; D002250:Carbon Radioisotopes; D003952:Diagnostic Imaging / Q000295:instrumentation* / Q000379:methods; D005473:Fluoxetine / Q000031:analogs & derivatives; D007091:Image Processing, Computer-Assisted; D007700:Kinetics; D008024:Ligands; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D010215:Papio; D049268:Positron-Emission Tomography / Q000379:methods*; D000077593:Reboxetine; D012680:Sensitivity and Specificity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D002250:Carbon Radioisotopes; D008024:Ligands; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; C011386:nisoxetine; D000077593:Reboxetine