Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart

Farde, Lars; Halldin, Christer; N�gren, Kjell; Suhara, Tetsuya; Karlsson, Per; Schoeps, Karl-Olof; Swahn, Carl‐Gunnar; Bone, D.

doi:10.1007/bf00176575

Cited by 3 publications

(3 citation statements)

References 7 publications

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“…Norepinephrine transport in sympathetic nerves of peripheral tissues has been labeled with (+/–)‐[ 11 C]norepinephrine (Fowler et al . 1974; Farde et al . 1994), [ 18 F]fluoronorepinephrine (Ding et al .…”

Section: Affinity and Selectivity Of Several Potent Net Ligandsmentioning

confidence: 99%

Comparative evaluation of positron emission tomography radiotracers for imaging the norepinephrine transporter: (S,S) and (R,R) enantiomers of reboxetine analogs ([¹¹C]methylreboxetine, 3‐Cl‐[¹¹C]methylreboxetine and [¹⁸F]fluororeboxetine), (R)‐[¹¹C]nisoxetine, [¹¹C]oxaprotiline and [¹¹C]lortalamine

Ding

Lin

Logan

et al. 2005

Journal of Neurochemistry

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We have synthesized and evaluated several new ligands for imaging the norepinephrine transporter (NET) system in baboons with positron emission tomography (PET). Ligands possessing high brain penetration, high affinity and selectivity, appropriate lipophilicity (log P = 1.0–3.5), high plasma free fraction and reasonable stability in plasma were selected for further studies. Based on our characterization studies in baboons, including 11C‐labeled (R)‐nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and new analogs of methylreboxetine (MRB), in conjunction with our earlier evaluation of 11C and 18F derivatives of reboxetine, MRB and their individual (R,R) and (S,S) enantiomers, we have identified the superiority of (S,S)‐[11C]MRB and the suitability of MRB analogs [(S,S)‐[11C]MRB > (S,S)‐[11C]3‐Cl‐MRB > (S,S)‐[18F]fluororeboxetine] as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than in thalamus). The use of these ligands is further limited by high non‐specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge (S,S)‐[11C]MRB remains by far the most promising NET ligand for PET studies.

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Section: Affinity and Selectivity Of Several Potent Net Ligandsmentioning

confidence: 99%

Comparative evaluation of positron emission tomography radiotracers for imaging the norepinephrine transporter: (S,S) and (R,R) enantiomers of reboxetine analogs ([¹¹C]methylreboxetine, 3‐Cl‐[¹¹C]methylreboxetine and [¹⁸F]fluororeboxetine), (R)‐[¹¹C]nisoxetine, [¹¹C]oxaprotiline and [¹¹C]lortalamine

Ding

Lin

Logan

et al. 2005

Journal of Neurochemistry

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“…Racemic norepinephrine has recently been labeled with carbon-11 1 and used as a ligand to visualize the uptake in sympathetic nerve terminals of primate myocardium. 10 Accordingly, the effect of cocaine on ["C]norepinephrine uptake can be directly demonstrated by PET.…”

Section: Introductionmentioning

confidence: 99%

Effects of cocaine on [11C]norepinephrine and [11C]β-CIT uptake in the primate peripheral organs measured by PET

et al. 1996

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The toxic properties of cocaine are related to both the central and peripheral effects. To identify possible lethal mechanisms and the accumulation of cocaine in various organs, the effects of cocaine on [11C]norepinephrine and cocaine congener [11C] beta-CIT uptake in Cynomolgus monkeys were measured by positron emission tomography (PET). Cocaine (5 mg/kg) noticeably inhibited [11C]norepinephrine uptake in the heart. The uptake of [11C] beta-CIT in the heart and lung was reduced by pretreatment with cocaine. There was a significant uptake in the liver which was increased following cocaine pretreatment. The results of this study confirm that cocaine blocks the neuronal uptake of norepinephrine in sympathetic nerve terminals in the myocardium. The effect of cocaine on [11C] beta-CIT uptake indicates that the binding sites in the heart and lung are saturable, while the uptake mechanism in the liver is different from those of the heart and lung.

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“…Norepinephrine has been labeled with C-11 ((±)- [ 11 C]NE) [24,25] [32], [ 11 C]phenylephrine [33], [ 11 C]meta-hydroxyephedrine [34], have been developed for PET studies of sympathetic innervation in the heart; however, their use as tracers to study brain NET is limited due to their inability to cross the blood-brain barrier. Several potent NET reuptake inhibitors have been labeled for in vitro or in vivo mapping of brain NET; however, the results were not promising due to their high non-specific bindings.…”

Section: Introductionmentioning

confidence: 99%

PET Imaging of Norepinephrine Transporters

Ding¹,

Lin²,

Logan³

2006

CPD

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Abstract:The involvement of the norepinephrine transporter (NET) in the pathophysiology and treatment of attention deficit hyperactivity disorder (ADHD), substance abuse, neurodegenerative disorders (e.g., Alzheimer's disease (AD) and Parkinson's disease (PD)) and depression has long been recognized. However, many of these important findings have resulted from studies in vitro using postmortem tissues; as of now, these results have never been verified via in vivo methods because brain imaging of NET in living systems has been hampered due to the lack of suitable radioligands. The fact that all three monoamine (dopamine, norepinephrine, and serotonin) transporters (DAT, NET and SERT) are involved in various neurological and psychiatric diseases further emphasizes the need to develop suitable NET ligands so that researchers will be able to probe the contributions of each monoamine transporter system to specific CNS disorders. In this review article, the design and biological evaluation of several radioligands for imaging the brain NET system with PET are discussed. Based on these characterization studies, including C-11 labeled desipramine (DMI), 2-hydroxydesipramine (HDMI), talopram, talsupram, nisoxetine (Nis), oxaprotiline (Oxap), lortalamine (Lort) and C-11 and F-18 derivatives of reboxetine (RB), methylreboxetine (MRB) and their individual (R, R) and (S, S) enantiomers, in conjunction with studies with radiolabeled 4-iodo-tomoxetine and 2-iodo-nisoxetine, we have identified the superiority of (S, S)-[11 C]MRB and the suitability of the MRB analogs as potential NET ligands for PET. In contrast, Nis, Oxap and Lort displayed high uptake in striatum (higher than thalamus). The use of these ligands is further limited by high non-specific binding and relatively low specific signal, as is characteristic of many earlier NET ligands. Thus, to our knowledge, (S, S)-[11 C]MRB remains by far the most promising NET ligand for PET studies.

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Positron emission tomography shows high specific uptake of racemic carbon-11 labelled norepinephrine in the primate heart

Cited by 3 publications

References 7 publications

Effects of cocaine on [11C]norepinephrine and [11C]β-CIT uptake in the primate peripheral organs measured by PET

PET Imaging of Norepinephrine Transporters

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