Synthesis, radiosynthesis, and biological evaluation of carbon-11 and fluorine-18 labeled reboxetine analogues: potential positron emission tomography radioligands for in vivo imaging of the norepinephrine transporter.
Reboxetine analogues with methyl and fluoroalkyl substituents at position 2 of the phenoxy ring 1-4 were synthesized. In vitro competition binding with [(3)H]nisoxetine demonstrated that 1-4 have a high affinity for the norepinephrine transporter (NET) with K(i)'s = 1.02, 3.14, 3.68, and 0.30 nM, respectively. MicroPET imaging in rhesus monkeys showed that the relative regional distribution of [(11)C]1 and [(11)C]4 is consistent with distribution of the NET in the brain, while [(18)F]2 and [(18)F]3 showed only slight regional differentiation in brain uptake. Especially, the highest ratios of uptake of [(11)C]1 in NET-rich regions to that in caudate were obtained at 1.30-1.45 at 45 min and remained relatively constant over 85 min. Pretreatment of the monkey with the selective NET inhibitor, desipramine, decreased the specific binding for both [(11)C]1 and [(11)C]4. PET imaging in awake monkeys suggested that anesthesia influenced the binding potential of [(11)C]1 and [(11)C]4 at the NET.
Zeng
Fanxing
F
Department of Radiology, Yerkes Regional Primate Research Center, Emory University, Atlanta, Georgia 30322, USA.
Mun
Jiyoung
J
Jarkas
Nachwa
N
Stehouwer
Jeffrey S
JS
Voll
Ronald J
RJ
Tamagnan
Gilles D
GD
Howell
Leonard
L
Votaw
John R
JR
Kilts
Clinton D
CD
Nemeroff
Charles B
CB
Goodman
Mark M
MM
D000818:Animals; D002250:Carbon Radioisotopes; D002460:Cell Line; D005462:Fluorine Radioisotopes; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D015394:Molecular Structure; D009025:Morpholines / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000032:analysis* / Q000138:chemical synthesis* / Q000737:chemistry; D000077593:Reboxetine; D013237:Stereoisomerism
D002250:Carbon Radioisotopes; D005462:Fluorine Radioisotopes; D009025:Morpholines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D019275:Radiopharmaceuticals; D000077593:Reboxetine