TY - JOUR T1 - Human PET studies of the norepinephrine transporter (NET) with (S,S)-[11C]O-methyl reboxetine ([11C](S,S)-MRB) and PET JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 61P LP - 61P VL - 48 IS - supplement 2 AU - Jean Logan AU - Gene-Jack Wang AU - Joanna Fowler AU - Yu-Shin Ding AU - David Alexoff AU - John Zabroski AU - Susan Learned-Coughlin AU - Nora Volkow Y1 - 2007/05/01 UR - http://jnm.snmjournals.org/content/48/supplement_2/61P.2.abstract N2 - 203 Objectives: Human studies with [11C](S,S)-MRB, a NET radiotracer, were done to assess regional distribution, kinetics, reproducibility and sensitivity to blockade with the high affinity NET drug atomoxetine (ATX). Methods: Twenty four male subjects underwent 90-minute PET scans to assess reproducibility and dose dependency of blockade with ATX (25, 50 and 100 mg po,1 hr prior). Region of interest (ROI) uptake data and arterial plasma input were analyzed for the distribution volume (DV). Images were normalized to a template and average parametric images for each group were formed. Results: [11C](S,S)-MRB uptake was highest in thalamus (THL) and midbrain (MBR) (containing the locus coeruleus(LC)) and lowest for caudate nucleus (CDT). The CDT showed the smallest change on ATX treatment and was used as a reference region for the DV ratio (DVR). The baseline average DVR was 1.48 for both THL and MBR, other regions were lower (cerebellum 1.09). However MBR exhibited greater blocking (avg decrease 28±10%) than THL (17±10%) indicating a transporter density ~40% greater than THL. There was no relationship between DVR change and plasma ATX level. Only for MBR did % change across subjects correlate with ATX dose but not significantly (average decrease for 25mg = 24 ± 7%; 50mg 27 ± 11%; 100mg = 31 ± 11%). Threshold analysis of the difference between the average baseline DV image and the average blocked image showed the expected NET distribution with the MBR (LC) and hypothalamus>THL>CB as well as a significant change in the supplementary motor area. DVR reproducibility for the different brain regions was ~10% but intersubject variability was large. Conclusions: The highest density of NET’s was found in MBR and the lowest density in CDT consistent with regional localization of NETS in brain. The lack of a dose effect could reflect a low signal to noise ratio coupled with the possibility that a sufficient number of transporters were blocked at the lowest dose and further differences could not be detected. However since the lowest dose is less than common therapeutic doses, there may be additional targets for ATX. Research Support (if any): DOE-OBER, GSK, NIAAA, NIBIB ER -