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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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(2S,3S)-2-[α-(2-[11C]Methylphenoxy)phenylmethyl]morpholine

[11C]MENET-1
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 15, 2009.

Chemical name:(2S,3S)-2-[α-(2-[11C]Methylphenoxy)phenylmethyl]morpholineimage 57570843 in the ncbi pubchem database
Abbreviated name:[11C]MENET-1
Synonym:(2S)-2-[(S)-(2-methylphenoxy)-phenylmethyl]morpholine
Agent category:Compound
Target:Norepinephrine transporter (NET)
Target category:Transporter
Method of detection:Positron emission tomography (PET)
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Non-human primates
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Many diseases affect the sympathetic nervous system (SNS), and imaging of pathological changes of adrenergic transmission has been an important area of radiopharmaceutical research (1, 2). Most postganglionic sympathetic neurons in the autonomic nervous system release the neurotransmitter norepinephrine (NE), which stimulates adrenergic receptors in various effector organs (3). There are different types and subtypes of adrenergic receptors, and they are characterized as α1a to α1c, α2a to α2c, and β1 to β3 (4). All of the NE adrenergic receptors belong to the G-protein–linked receptor superfamily and mediate slow neuromodulatory postsynaptic responses. The NE transporter (NET) is a transmembrane protein located in the adrenergic nerve terminals, and it is responsible for active reuptake (uptake-1) of NE released from neurons (5). NE is stored in the neuronal vesicles and is released on stimulation. Significant expression of NET is found in major organs of the SNS, such as the heart and brain. There is substantial evidence that aberrations in cardiac SNS function contribute to the morbidity and mortality associated with cardiac diseases (6). Brain NET is involved in various neurological and psychiatric diseases, including depression, attention deficit hyperactivity disorder, drug addiction, and eating disorders (7). NET is also the site of action in the brain for many antidepressant drugs (8).

Molecular probes with structures closely related to NE can be used to assess the integrity of presynaptic sympathetic nerve terminals in various diseases. In vivo NE synthesis is similar to dopamine synthesis, and dopamine is converted to NE by the enzyme dopamine-β-hydroxylase (4). [123I]-meta-Iodobenzylguanidine, [11C]meta-hydroxyephedrine, [11C]norepinephrine, and many other radioligands have been developed and used for peripheral neuronal imaging (9). However, this class of tracers is not suitable for the study of brain NET system because they are not able to cross the blood–brain barrier (10). In the brain, NET levels are relatively low compared with those of other transporters, such as dopamine transporter (DAT) and serotonin transporter (SERT) (8). Several NET reuptake inhibitors such as [11C]desipramine have been tested, but they showed high nonspecific binding. Reboxetine ((RS)-2-[((RS)-2-ethoxyphenoxy)benzyl]morpholine) is a specific NET inhibitor with a high affinity and selectivity. Reboxetine is available as a racemic mixture of the (R,R) and (S,S) enantiomers. The (S,S) enantiomer has been found to be more potent, with a 50% inhibition concentration (IC50) value of 3.6 nM, for inhibiting NET in rat hypothalamic synaptosomes. Among the different reboxetine derivatives that have been tested, (2S,3S)-2-[α-(2-methylphenoxy)phenylmethyl]morpholine (MENET-1) is considered a potential candidate to be developed as a radioligand for studying the brain NET system (11). 11C-Labeled MENET-1 ([11C]MENET-1) is being developed as a positron emission tomography (PET) imaging agent of NET. 11C is a positron emitter with a physical half-life (t½) of 20.4 min.

Synthesis

[PubMed]

Zeng et al. (11) reported the two-step radiosynthesis of [11C]MENET-1 by 11C methylation of the N-Boc precursor (2S,3S)-N-tert-butoxycarbonyl-2-[α-(2-trimethylstannylphenoxy)phenylmethyl]morpholine and subsequent hydrolysis to remove the N-Boc protecting group. The N-Boc precursor was reacted with [11C]CH3I for 5 min at 100ºC in the presence of Pd2(dba)3, (o-CH3C6H4)3P, CuCl, and K2CO3, followed by removal of the N-Boc group with trifluoroacetic acid (7 min at 100ºC). Radiochemical yields were 38% (decay-corrected, based on [11C]CH3I), and the synthesis time was 60 min from the end of bombardment. After purification with high-performance liquid chromatography, the final product had a radiochemical purity of >98%. The specific activity was 14.8–33.3 GBq/μmol (0.4–0.9 Ci/μmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Zeng et al. (11) showed that binding affinities (Ki) of MENET-1 at NET, SERT, and DAT were 1.02 ± 0.11, 93 ± 20, and 327 ± 39 nM, respectively. The binding assays were performed using HEK-293 cells transfected with the human transporters. MENET-1 exhibited a log P7.4 of 2.04.

Animal Studies

Rodents

[PubMed]

No publication is currently available.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

Zeng et al. (11) evaluated [11C]MENET-1 as a radioligand for PET imaging studies of brain NET in male rhesus monkeys. Imaging studies with 555–740 MBq (15–20 mCi) [11C]MENET-1 showed high accumulation in the thalamus, midbrain, cerebellum, and pons (NET-rich regions) and moderate accumulation in the caudate and frontal cortex. The accumulation of radioactivity in the NET-rich regions peaked between 16–28 min after injection with a clearance t½ from peak uptake of ~105 min. The ratios of radioactivity in the NET-rich regions to caudate were 1.30–1.45 at 45 min and remained relatively constant (1.25–1.44) at 85 min. Pretreatment with desipramine (0.25 mg/kg) 40 min before [11C]MENET-1 injection led to reduced radioactivity levels in the NET-rich regions, but not in the caudate or occipital cortex. The ratios of radioactivity in the NET-rich regions to caudate were reduced to 0.79–1.06 at 85 min after injection.

The norepinephrine transporter in the monkey brain was distributed heterogeneously, with highest levels occurring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline thalamic nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala, and brainstem nuclei such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract. Low levels of binding to the norepinephrine transporter were measured in basolateral amygdala and cortical, hippocampal, and striatal regions. The distribution of the norepinephrine transporter in the non-human primate brain was comparable overall to that described in other species.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Konishi, J., B.A. Dwamena, M.D. Gross, B. Shapiro, T. Misaki, M. Fukunaga, J.C. Sisson, H.-Y. Oei, M. De Jong, and E. P. Krenning Endocrinology, in Molecular Nuclear Medicine, L.E. Feinendegen, W.W. Shreeve, W.C. Eckelman, Y.-W. Bahk, and H.N. Wagner Jr., Editor. 2003, Springer: New York. p. 357-409.
2.
Antoni, G., T. Kihlberg, and B. Langstrom, Aspects on the synthesis of 11C-Labelled compounds, in Handbook of Radiopharmaceuticals, M.J. Welch, and C.S. Redvanly, Editor. 2003, John Wiley & Sons Ltd.: West Sussex, England. p. 141-194.
3.
Sunderland, P.M., Pathophysiology. The biologic basis for disease in adults and children, K.L. McCance, and S. E. Huether, Editor. 1994, Mosby-Year Books, Inc.: St, Louiis. p. 397-436.
4.
Frey, K.A., PET study of neurochemical systems, in Positron Emission Tomography, P.E. Valk, D.L. Bailey, D.W. Townsend, and M.N. Maisey, Editors. 2002, Springer London. p. 309-327.
5.
Buursma A.R., Beerens A.M., de Vries E.F., van Waarde A., Rots M.G., Hospers G.A., Vaalburg W., Haisma H.J. The Human Norepinephrine Transporter in Combination with 11C-m-Hydroxyephedrine as a Reporter Gene/Reporter Probe for PET of Gene Therapy. J Nucl Med. 2005;46(12):2068–75. [PubMed: 16330572]
6.
Caldwell J.H., Kroll K., Li Z., Seymour K., Link J.M., Krohn K.A. Quantitation of presynaptic cardiac sympathetic function with carbon-11-meta-hydroxyephedrine. J Nucl Med. 1998;39(8):1327–34. [PubMed: 9708501]
7.
Zahniser N.R., Doolen S. Chronic and acute regulation of Na+/Cl- -dependent neurotransmitter transporters: drugs, substrates, presynaptic receptors, and signaling systems. Pharmacol Ther. 2001;92(1):21–55. [PubMed: 11750035]
8.
Wilson A.A., Johnson D.P., Mozley D., Hussey D., Ginovart N., Nobrega J., Garcia A., Meyer J., Houle S. Synthesis and in vivo evaluation of novel radiotracers for the in vivo imaging of the norepinephrine transporter. Nucl Med Biol. 2003;30(2):85–92. [PubMed: 12623106]
9.
Langer O., Halldin C. PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging. 2002;29(3):416–34. [PubMed: 12002720]
10.
Ding Y.S., Lin K.S., Logan J., Benveniste H., Carter P. 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. J Neurochem. 2005;94(2):337–51. [PubMed: 15998285]
11.
Zeng F., Mun J., Jarkas N., Stehouwer J.S., Voll R.J., Tamagnan G.D., Howell L., Votaw J.R., Kilts C.D., Nemeroff C.B., Goodman M.M. 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. J Med Chem. 2009;52(1):62–73. [PMC free article: PMC2746395] [PubMed: 19067522]

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