Synthesis and PET evaluation of (R)‐[S‐methyl‐11C]thionisoxetine, a candidate radioligand for imaging brain norepinephrine transporters

Schou, Magnus; Pike, Victor W.; Varrone, Andrea; Gulyás, Balázs; Farde, Lars; Halldin, Christer

doi:10.1002/jlcr.1128

Cited by 15 publications

(13 citation statements)

References 42 publications

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“…In comparison to (S,S)-[ 11 C]MeNER 2, the corresponding (R)-[O- 11 CH 3 ] -nisoxetine derivative 6 ( Fig.1) exhibited very high non-specific binding in vivo [12,13]. None of the other 11 C labeled ligands for NET were as suitable as (S,S)-[ 11 C]MeNER 2 [14,15].…”

Section: Introductionmentioning

confidence: 99%

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Balagopal¹,

Kung²,

Lieberman³

et al. 2008

Nuclear Medicine and Biology

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Alterations in the serotonin and norepinephrine neuronal functions have been observed in patients with major depression. Several antidepressants bind to both serotonin transporters (SERT) and norepinephrine transporters (NET). The ability to image NET in the human brain would be a useful step toward understanding how alterations in NET relate to disease. In this study, we report the synthesis and characterization of a new series of derivatives of iodo-nisoxetine (INXT), a known radioiodinated probe. The most promising, (R)-N-methyl-3-(3-iodopyridin-2-yloxy)-3-phenylpropylamine (PYINXT) 9, displayed a high and saturable binding to NET with a K d value of 0.53 ± 0.03 nM. Biodistribution studies of [ 125 I]PYINXT in rats showed moderate initial brain uptake (0.54 %dose/organ at 2 min) with a relatively fast washout from the brain (0.16 %dose/organ at 2 hr) as compared to [ 125 I]INXT, 7. The hypothalamus (a NET rich region) to striatum (a region devoid of NET) ratio was found to be 2.14 at 4 hr post i.v. injection. The preliminary results suggest that this improved iodinated ligand, when labeled with 123 I, may be useful for mapping NET binding sites with SPECT in the living human brain.

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Section: Introductionmentioning

confidence: 99%

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Balagopal¹,

Kung²,

Lieberman³

et al. 2008

Nuclear Medicine and Biology

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“…Thus, rat brain has seven times more NAT binding sites than non‐human primate brain. It is worth noting that that the density of NATs in human cerebral cortex is approximately nine times lower than in rodents (Schou et al, 2006). Consequently, the present results obtained with 123 I‐NKJ64 in baboons, and the known differences in NAT densities across species, preclude the translation of 123 I‐NKJ64 for use in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple NAT‐selective radiotracers have been developed over the years for in vivo and in vitro brain imaging, including: 11 C‐desipramine ( 11 C‐DMI) and its hydroxylated derivate ( R )‐ 11 C‐OHDMI; 11 C‐nisoxetine and its derivatives ( 125 I‐INXT and 125 I‐PYINXT); 11 C‐thionisoxetine; 11 C‐oxaprotiline; 11 C‐lortalamine; 11 C‐talopran; 11 C‐talsupran; two 11 C‐labeled analogues of mazindol; and 11 C‐labelled, 18 F‐labeled and 123 I‐labeled analogues of reboxetine (McConathy et al,2004; Schou et al,2006,2007;2006; Zeng et al,2009). The most promising PET radiotracers developed for in vivo imaging of the NAT are analogues of reboxetine and include: ( S , S )‐ 11 C‐MeNER, ( S , S )‐ 18 F‐FMeNER‐D 2 , and ( S , S )‐ 18 F‐FRB‐D 4 (Schou et al,2006,2007). For in vivo imaging of the NAT using SPECT, the most promising radiotracers developed to date are also reboxetine analogues, namely 123 I‐INER (also denoted ( S , S )‐IPBM) (Kanegawa et al,2006; Tamagnan et al,2007) and 123 I‐NKJ64 (Tavares et al,2011a) (Fig.…”

Section: Introductionmentioning

confidence: 99%

Iodine‐123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Tavares

Jobson

Dewar

et al. 2012

Synapse

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(2012) Iodine-123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography. Synapse, 66 (11). pp. [923][924][925][926][927][928][929][930] Copyright © 2012 Wiley Periodicals, Inc A copy can be downloaded for personal non-commercial research or study, without prior permission or chargeThe content must not be changed in any way or reproduced in any format or medium without the formal permission of the copyright holder(s) When referring to this work, full bibliographic details must be given http://eprints.gla.ac.uk/68100 may lack affinity and selectivity for NAT in baboon brain and 123 I-INER is the most promising iodinated reboxetine analogue developed to date for in vivo imaging of NAT in brain using SPECT. This study highlights the importance of species differences during radiotracer development and the stereochemical configuration of analogues of reboxetine in vivo.

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“…Further monocyclic NET radioligands that have been reported are (R)-[ 11 C]thionisoxetine and two 11 C-labeled piperidine-based analogues of cocaine (1 and 2, Fig. 2) [64,80]. Whereas the first mentioned ligand did not show improved target to non-target ratios with respect to the reboxetine analogues [90], the piperidine based radioligands predominantly showed binding to DAT [64,80].…”

Section: Tricyclics Tropanesmentioning

confidence: 92%

Development of Radioligands for Imaging of Brain Norepinephrine Transporters In Vivo with Positron Emission Tomography

Schou¹,

Pike²,

Halldin³

2007

CTMC

Self Cite

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In the central nervous system (CNS) and in the periphery, specific proteins (transporters) are responsible for the regulation of the synaptic concentrations of the major monoamine neurotransmitters, noradrenaline (NE), serotonin (5-HT) and dopamine (DA). Several reports have shown that the expression of these transporters within the CNS may be altered in patients with certain neurodegenerative or neuropsychiatric disorders. Therefore, in the CNS the monoamine transporters are major targets for existing and developmental drugs. The best known drugs targeting these transporters are the selective 5-HT reuptake inhibitors (SSRIs) (e.g. citalopram, Celexa) that are most frequently used in the treatment of clinical depression. Selective NE reuptake inhibitors (NRIs) have also found use for the treatment of depression and other conditions such as attention deficit hyperactivity (ADHD) disorder. Given that the NE transporter (NET) is also a binding site for cocaine and drugs of abuse, there is a great need for a probe to assess the densities of NET in vivo by brain imaging with either positron emission tomography (PET) or single photon emission tomography (SPET). PET in particular has the potential to measure NET densities quantitatively and with high resolution in the human brain in vivo. The quality of a PET image depends crucially on the radioligand used in the emission measurement. Commonly used radionuclides in PET radioligands are carbon 11 (t(1/2) = 20.4 min) and fluorine-18 (t(1/2) = 109.8 min). This review specifically summarizes the present status of the development of (11)C- or (18)F-labeled ligands as tools for imaging NET in brain with PET in support of neuropsychiatric clinical research and drug development.

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Synthesis and PET evaluation of (R)‐[S‐methyl‐¹¹C]thionisoxetine, a candidate radioligand for imaging brain norepinephrine transporters

Cited by 15 publications

References 42 publications

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

(R)-N-Methyl-3-(3-125I-pyridin-2-yloxy)-3-phenylpropan-1-amine: a novel probe for norepinephrine transporters

Iodine‐123 labeled reboxetine analogues for imaging of noradrenaline transporter in brain using single photon emission computed tomography

Development of Radioligands for Imaging of Brain Norepinephrine Transporters In Vivo with Positron Emission Tomography

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