PET imaging of the effects of age and cocaine on the norepinephrine transporter in the human brain using (S,S)-[(11)C]O-methylreboxetine and HRRT.
OBJECTIVE
The role of the norepinephrine transporter (NET) in cocaine dependence has never been demonstrated via in vivo imaging due to the lack of suitable NET radioligands. Here we report our preliminary studies evaluting the NET in individuals with cocaine dependence (COC) in comparison to healthy controls (HC) using (S,S)-[(11)C]methylreboxetine ([(11)C]MRB), the most promising C-11 labeled positron-emission tomography (PET) radioligand for NET developed to date.


METHODS
Twenty two human volunteers (10 COC and 12 HC) underwent dynamic (11)C-MRB-PET acquisition using a High Resolution Research Tomograph (HRRT). Binding potential (BP(ND)) parametric images were computed using the simplified reference tissue model (SRTM2) with occipital cortex as reference region. BP(ND) values were compared between the two groups.


RESULTS
Locus coeruleus (LC), hypothalamus, and pulvinar showed a significant inverse correlation with age among HC (age range = 25-54 years; P = 0.04, 0.009, 0.03 respectively). The BP(ND) was significantly increased in thalamus (27%; P < 0.02) and dorsomedial thalamic nuclei (30%; P < 0.03) in COC as compared to HC. Upon age normalization, the upregulation of NET in COC also reached significance in LC (63%, P < 0.01) and pulvinar (55%, P < 0.02) regions.


CONCLUSIONS
Our results suggest that (a) brain NET concentration declines with age in HC, and (b) there is a significant upregulation of NET in thalamus and dorsomedial thalamic nucleus in COC as compared to HC. Our results also suggest that the use of [(11)C]MRB and HRRT provides an effective strategy for studying alterations of the NET system in humans.
Ding
Yu-Shin
YS
Yale PET Center, Department of Diagnostic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520-8048, USA. yu-shin.ding@yale.edu
Singhal
Tarun
T
Planeta-Wilson
Beata
B
Gallezot
Jean-Dominique
JD
Nabulsi
Nabeel
N
Labaree
David
D
Ropchan
Jim
J
Henry
Shannan
S
Williams
Wendol
W
Carson
Richard E
RE
Neumeister
Alexander
A
Malison
Robert T
RT
D000328:Adult; D000375:Aging / Q000502:physiology; D001921:Brain / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000009:adverse effects; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008297:Male; D008875:Middle Aged; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals; D000077593:Reboxetine
D018765:Dopamine Uptake Inhibitors; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; C524178:O-methyl reboxetine; D019275:Radiopharmaceuticals; D000077593:Reboxetine; D003042:Cocaine