Alin J Severance1, Matthew S Milak2,1, J S Dileep Kumar2,1, Jaya Prabhakaran2, Vattoly J Majo2, Norman R Simpson3, Ronald L Van Heertum3, Victoria Arango2,1, J John Mann2,3,1, Ramin V Parsey4,5. 1. Division of Brain Imaging, Department of Neuroscience, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box #42, New York, NY, 10032, USA. 2. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. 3. Department of Radiology, Columbia University College of Physicians and Surgeons, New York, NY, USA. 4. Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York, NY, USA. rparsey@neuron.cpmc.columbia.edu. 5. 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.
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 [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.
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 [(11)C]MRB lacks sensitivity and reliability as a PET radiotracer in humans.
Authors: Nicholas Seneca; Balázs Gulyás; Andrea Varrone; Magnus Schou; Anu Airaksinen; Johannes Tauscher; Francois Vandenhende; William Kielbasa; Lars Farde; Robert B Innis; Christer Halldin Journal: Psychopharmacology (Berl) Date: 2006-08-04 Impact factor: 4.530
Authors: Matthew S Milak; R Todd Ogden; Daniel N Vinocur; Ronald L Van Heertum; Thomas B Cooper; J John Mann; Ramin V Parsey Journal: Biol Psychiatry Date: 2005-01-01 Impact factor: 13.382
Authors: Christoph Schroeder; Frauke Adams; Michael Boschmann; Jens Tank; Sebastian Haertter; Andre Diedrich; Italo Biaggioni; Friedrich C Luft; Jens Jordan Journal: Am J Physiol Regul Integr Comp Physiol Date: 2004-01-15 Impact factor: 3.619
Authors: Robert Risinger; Zubin Bhagwagar; Feng Luo; Matthew Cahir; Laura Miler; Anisha E Mendonza; Jeffrey H Meyer; Ming Zheng; Wendy Hayes Journal: Psychopharmacology (Berl) Date: 2013-12-15 Impact factor: 4.530
Authors: Fanxing Zeng; Jiyoung Mun; Nachwa Jarkas; Jeffrey S Stehouwer; Ronald J Voll; Gilles D Tamagnan; Leonard Howell; John R Votaw; Clinton D Kilts; Charles B Nemeroff; Mark M Goodman Journal: J Med Chem Date: 2009-01-08 Impact factor: 7.446