Synthesis and evaluation of racemic [(11)C]NS2456 and enantiomers as selective serotonin reuptake radiotracers for PET.
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Synthesis and evaluation of racemic [(11)C]NS2456 and enantiomers as selective serotonin reuptake radiotracers for PET. / Smith, D F; Bender, D; Marthi, K; Cumming, P; Hansen, Søren Baarsgaard; Peters, D; Nielsen, E O; Scheel-Krüger, J; Gjedde, A.
In: Nuclear Medicine and Biology, Vol. 28, No. 3, 2001, p. 265-70.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Synthesis and evaluation of racemic [(11)C]NS2456 and enantiomers as selective serotonin reuptake radiotracers for PET.
AU - Smith, D F
AU - Bender, D
AU - Marthi, K
AU - Cumming, P
AU - Hansen, Søren Baarsgaard
AU - Peters, D
AU - Nielsen, E O
AU - Scheel-Krüger, J
AU - Gjedde, A
PY - 2001
Y1 - 2001
N2 - Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC(50) values were 3000-fold lower for [(3)H]serotonin than for either [(3)H]dopamine or [(3)H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [(11)C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [(11)C]NS2456 nor its [(11)C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.
AB - Positron emission tomography (PET) radiotracers are needed for quantifying serotonin uptake sites in the living brain. Therefore, we evaluated a new selective serotonin reuptake inhibitor, NS2456, to determine whether it is suited for use in PET. Racemic NS2456 [(1RS,5SR)-8-methyl-3-[4-trifluoromethoxyphenyl]-8-azabicyclo [3.2.1]oct-2-ene] and its N-demethylated analog, racemic NS2463, selectively inhibited serotonin uptake in rat brain synaptosomes; their IC(50) values were 3000-fold lower for [(3)H]serotonin than for either [(3)H]dopamine or [(3)H]noradrenaline. The enantiomers of NS2463 were also potent inhibitors of serotonin uptake in vitro, but they failed to show stereoselectivity. Racemic NS2463 as well as its enantiomers were radiolabelled by N-methylation with C-11, yielding [(11)C]NS2456 for use in PET of the living porcine brain. The compounds crossed the blood-brain barrier rapidly and accumulated preferentially in regions rich in serotonin uptake sites (e.g., brainstem, subthalamus and thalamus). However, their binding potentials were relatively low and no stereoselectivity was found. Thus, neither racemic [(11)C]NS2456 nor its [(11)C]-labelled enantiomers are ideal for PET neuroimaging of neuronal serotonin uptake sites.
M3 - Journal article
C2 - 11323236
VL - 28
SP - 265
EP - 270
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
SN - 0969-8051
IS - 3
ER -
ID: 14947000