Kanegawa N, Kiyono Y, Kimura H, Sugita T, Kajiyama S, Kawashima H et al. Synthesis and evaluation of radioiodinated (S,S)-2-(α-(2-iodophenoxy)benzyl)morpholine for imaging brain norepinephrine transporter. Eur J Nucl Med Mol Imaging 33: 639-647

Department of Patho-Functional Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
European journal of nuclear medicine and molecular imaging (Impact Factor: 5.38). 06/2006; 33(6):639-47. DOI: 10.1007/s00259-005-0017-y
Source: PubMed


Abnormality of the brain norepinephrine transporter (NET) has been reported in several psychiatric and neuronal disorders. Since NET is an important target for the diagnosis of these diseases, the development of radiopharmaceuticals for imaging of brain NET has been eagerly awaited. In this study, we synthesized (S,S)-2-(alpha-(2-iodophenoxy)benzyl)morpholine [(S,S)-IPBM], a derivative of reboxetine iodinated at position 2 of the phenoxy ring, and evaluated its potential as a radiopharmaceutical for imaging brain NET using SPECT.
(S,S)-(123/125)I-IPBM was synthesized in a halogen exchange reaction. The affinity and selectivity of (S,S)-IPBM for NET was measured by assaying the displacement of (3)H-nisoxetine and (S,S)-(125)I-IPBM from the binding site in rat brain membrane, respectively. The biodistribution of (S,S)-(125)I-IPBM was also determined in rats. Furthermore, SPECT studies with (S,S)-(123)I-IPBM were carried out in the common marmoset.
(S,S)-(125)I-IPBM was prepared with high radiochemical yields (65%) and high radiochemical purity (>98%). (S,S)-IPBM showed high affinity and selectivity for NET in the binding assay experiments. In biodistribution experiments, (S,S)-(125)I-IPBM showed rapid uptake in the brain, and the regional cerebral distribution was consistent with the density of NET. The administration of nisoxetine, a selective NET-binding agent, decreased the accumulation of (S,S)-(125)I-IPBM in the brain, but the administration of selective serotonin transporter and dopamine transporter binding agents caused no significant changes in the accumulation. Moreover, (S,S)-(123)I-IPBM allowed brain NET imaging in the common marmoset with SPECT.
These results suggest that (S,S)-(123)I-IPBM is a potential SPECT radiopharmaceutical for imaging brain NET.

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    • "The incidence of seizures during treatment with NRIs has been reportedly rare (Montgomery, 2005; Wernicke et al, 2007). Brain levels of the drugs in overdose cases may be considerably higher than levels during treatment at therapeutic doses (Poggesi et al, 2000; Kiyono et al, 2004, 2008; Garside et al, 2006; Kanegawa et al, 2006), suggesting that potent inhibition of neuronal GIRK channels by atomoxetine and reboxetine after overdose may contribute to increased seizure activity. However, the NRIs simultaneously increase extracellular levels of norepinephrine in the brain (Hajós et al, 2004; Simpson and Plosker, 2004), and norepinephrine has anticonvulsant effects (Ahern et al, 2006). "
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    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2010; 35(7):1560-9. DOI:10.1038/npp.2010.27 · 7.05 Impact Factor
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    • "Ex vivo autoradiography Ex vivo autoradiography was performed using a previously described method (Kanegawa et al., 2006) with slight modifications . Three groups of rats, a sham-operated group, a 2 week and a 1 month post-PSL group, were used in this experiment. "
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    ABSTRACT: Much interest is currently being focused on the anti-nociceptive effects mediated by nicotinic acetylcholine (nACh) receptors, including their location and mechanism of action. The purpose of this study was to elucidate these issues using 5-iodo-3-(2(S)-azetidinylmethoxy)pyridine (5IA), a nACh receptor agonist, and [(125)I]5IA. We partially ligated the sciatic nerve of Sprague-Dawley rat to induce neuropathic pain [Seltzer's partial sciatic nerve ligation (PSL) model]. We then examined the changes in nACh receptor density in the CNS using [(125)I]5IA autoradiography and the involvement of nACh receptors in anti-nociceptive effects in the region where changes occurred. Autoradiographic studies showed that the accumulation of [(125)I]5IA and the number of nACh receptors in the thalamus of PSL rats were increased about twofold compared with those in the sham-operated rats. No change was observed in other brain regions. Rats injected in the ventral posterolateral thalamic nucleus (VPL) with 5IA demonstrated a significant and dose-dependent anti-allodynic effect and this effect was completely antagonized by mecamylamine, injected with 5IA, into the VPL. The blockade of nACh receptors in the VPL by mecamylamine decreased by 70% the anti-allodynic effect of 5IA, given i.c.v. Moreover, mecamylamine given intra-VPL by itself, induced significant hyperalgesia. Our findings suggest that the nACh receptors expressed in the VPL play an important role in the anti-allodynic effects produced by exogenous and endogenous agonists.
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    ABSTRACT: 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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