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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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, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: March 24, 2008.

Chemical name:(S,S)-2-(α-(2-[18F]Fluoro[2H2]methoxyphenoxy)benzyl)morpholineimage 11528972 in the ncbi pubchem database
Abbreviated name:(S,S)-[18F]FMeNER-D2
Agent Category:Compound
Target:Brain norepinephrine transporter (NET)
Target Category:Transporter binding
Method of detection:Positron Emission Tomography (PET)
Source of signal/contrast:18F
  • Checkbox In vitro
  • Checkbox Non-human primates
Click on the above structure for additional information in PubChem.



(S,S)-2-(α-(2-[18F]Fluoro[2H2]methoxyphenoxy)benzyl)morpholine ((S,S)-[18F]FMeNER-D2) is a radioligand developed for positron emission tomography (PET) imaging of the brain adrenergic receptors. It is a derivative of reboxetine ((RS)-2-[(RS)-2-ethoxyphenoxy)benzyl]morpholine), a norepinephrine transporter (NET) inhibitor, labeled with 18F, a positron emitter with a physical half-life (t½) of 109.8 min (1, 2).

Many diseases affect the sympathetic nervous system (SNS), and imaging of pathologic changes of adrenergic transmission has been an important area of PET research (3, 4). Most postganglionic sympathetic neurons in the autonomic nervous system release the neurotransmitter norepinephrine (NE), which stimulates adrenergic receptors in various effector organs (5). There are different types and subtypes of adrenergic receptors, and they are characterized as α1a to α1c, α2a to α2c, and β1 to β3 (6). All of the NE receptors belong to the G-protein-linked receptor superfamily and mediate slow neuromodulatory postsynaptic responses. The NET is a transmembrane protein located in the adrenergic nerve terminals that is responsible for active reuptake (uptake-1) of NE released from neurons (7). 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. Brain NETs are involved in various neurologic and psychiatric diseases, including depression, attention deficit hyperactivity disorder, drug addiction, and eating disorders (8). Brain NETs are also the site of action of many antidepressant drugs in the brain (9).

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 (6). [123I]-meta-Iodobenzylguanidine, [11C]m-hydroxyephedrine, [11C]norepinephrine, and many other radioligands have been developed and used for peripheral neuronal imaging (10). 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 (11). In the brain, NET levels are relatively lower than other receptors, such as dopamine transporters (DATs) and serotonin transporters. (9). Several NET reuptake inhibitors, such as [11C]desipramine, have been tested, but they showed high nonspecific binding. Reboxetine is a specific NET inhibitor with a high affinity and selectivity (inhibitory concentration (IC50) DAT/NET = 4,000). The (S,S)-MeNER enantiomer ((S,S)-MRB) is the more potent enantiomer with a IC50 of 3.6 nM for inhibiting NE uptake in rat hypothalamic synaptosomes. 11C-labeled (S,S)-MeNER has been shown to be a promising brain NET imaging agent, but the specific binding peak equilibrium could not be measured because of the short t½ of 11C. Because of the longer t½ of 18F, Shou et al. (1) described the synthesis of the first radiofluorinated ligand, (S,S)-[18F]FMeNER, for brain NET imaging. The di-deuterated analog, (S,S)-[18F]FMeNER-D2, was developed to minimize the in vivo defluorination of (S,S)-[18F]FMeNER (1).



(S,S)-[18F]FMeNER-D2 was prepared by O-fluoromethylation of the precursor, desfluoromethoxy-(S,S)-FMeNER, with [18F]fluorobromomethane-d2 (1). [18F]fluorobromomethane-d2 was prepared from [18F]fluoride ion (12). In this procedure, [18F]fluoride was isolated from a Sep-Pak QMA cartridge elution and was then reacted with dibromomethane-d2 in acetonitrile at 90 °C for 10-15 min. Desfluoromethoxy-(S,S)-FMeNER was reacted with [18F]bromofluoromethane-d2 in N,N-dimethylformamide at 90 °C for 5 min. (S,S)-[18F]FMeNER-D2 was purified by reverse-phase high-performance liquid chromatography. An alternative method involved reaction of [18F]fluoromethyl-d2 triflate with the N-Boc-protected precursor. The mixture was heated at 90 °C for 4 min.

The yield of [18F]fluorobromomethane-d2 was between 15 and 25% (noncorrected), and the subsequent yield of (S,S)-[18F]FMeNER-D2 was >90%. The overall yield of (S,S)-[18F]FMeNER-D2 from [18F]fluoride was between 5 and 10% with a total synthesis time of about 75 min. The radiochemical purity was >98%, and the specific activity at time of injection was about 111-185 GBq/μmol (3,000-5,000 Ci/mmol) in 0.08-0.2 μg of (S,S)-[18F]FMeNER-D2. The radioligand was stable in the phosphate-buffered saline formulation for the duration of the experiments. Radiochemical purity was >95% at 5 h after formulation.

In Vitro Studies: Testing in Cells and Tissues


Schou et al. (1, 13) performed in vitro autoradiography in human brains by incubating human brain sections with 4 MBq (0.11 mCi) of (S,S)-[18F]FMeNER-D2 for 90 min at room temperature. The study showed that (S,S)-[18F]FMeNER-D2 bound substantially to the cerebral and cerebellar gray matter but that binding to the white matter was lower. The binding was highest in the locus coeruleus. Lower binding was observed in the cerebellum, temporal cortex, and thalamus. The binding, expressed as percentage of locus coeruleus binding, was 15.2, 12.3, and 8.0 in the cerebellum, temporal cortex, and thalamus, respectively. This binding was blocked by 10 μM desipramine (selective NET inhibitor), but no inhibition was observed with the DAT inhibitor PE2I or the serotonin transporter inhibitor citalopram.

Animal Studies



No publication is currently available.

Other Non-Primate Mammals


No publication is currently available.

Non-Human Primates


Schou et al. (1) performed (S,S)-[18F]FMeNER-D2 PET imaging in two female cynomolgus monkeys. In each study, 49-68 MBq (1.3-1.8 mCi) of (S,S)-[18F]FMeNER-D2 was injected as a bolus. After injection at baseline conditions, the maximum activity in the monkey brain was ~3.6% of the total radioactivity 12 min after administration. The radioactivity was highest in the temporal cortex and lowest in the striatum. An equilibrium specific binding peak of the whole brain was observed between 120 and 160 min. The equilibrium specific binding peak was achieved in about 150 min in the temporal cortex. At 160 min, the region/striatum ratios were 1.5, 1.6, 1.3, and 1.5 for the lower brainstem, mesencephalon, thalamus, and temporal cortex, respectively. In comparison, (S,S)-[18F]FMeNER injection revealed skull-bound radioactivity that contaminated the brain images because of in vivo defluorination. Pretreatment with 5 mg/kg desipramine 20 min before (S,S)-[18F]FMeNER-D2 injection blocked radioactivity uptake in all regions. HPLC analysis of plasma samples showed that 85 ± 3% (n = 4) of (S,S)-[18F]FMeNER-D2 remained unchanged at 45 min and 76 ± 6% (n = 3) at 90 min.

Seneca et al. (2) reported whole-body distribution and radiation dosimetry of (S,S)-[18F]FMeNER-D2 in two female cynomolgus monkeys. The monkeys received doses of 65 MBq (1.8 mCi) and 76.4 MBq (2.1 mCi). The peak percentages of injected dose (% ID) in the lungs, kidneys, brain, liver, red bone marrow, heart, and urinary bladder were 26.8, 13.6, 5.7, 7.2, 5.0, 2.4, and 23% ID at peak times 1.42, 2.18, 4.48, 2, 2.06, 1.42, and 250 min, respectively. The cumulative urine excretion was 20.8% ID at 150 min. The effective t½ in the bladder was 0.649 h. The liver also showed rapid elimination with about two thirds of the liver radioactivity going to the gastrointestinal tract during the first 4 h. Calculations performed with the MIRDOSE 3.1 program indicated that the kidney was the critical organ, with 126 μGy/MBq (468 mrad/mCi), based on 2.4 h voiding intervals. The other organs with relatively higher doses (2.4 h voiding intervals) were the urinary bladder wall (114 μGy/MBq (422 mrad/mCi)), the heart wall (108 μGy/MBq (399 mrad/mCi)), the lungs (88.4 μGy/MBq (327 mrad/mCi)), the liver (28.3 μGy/MBq (105 mrad/mCi)), the upper large intestine (28.1 μGy/MBq (104 mrad/mCi)), the brain (27.6 μGy/MBq (102 mrad/mCi)), the small intestine 26.2 μGy/MBq (96.8 mrad/mCi)), and the bone marrow (22.2 μGy/MBq (82 mrad/mCi)).

Human Studies


No publication is currently available.

NIH Support

NIN Intramural Support, KI(Karolinska Institutet)-NIH Graduate Training Partnership.


Schou M., Halldin C., Sovago J., Pike V.W., Hall H., Gulyas B., Mozley P.D., Dobson D., Shchukin E., Innis R.B., Farde L. PET evaluation of novel radiofluorinated reboxetine analogs as norepinephrine transporter probes in the monkey brain. Synapse. 2004;53(2):57–67. [PubMed: 15170818]
Seneca N., Andree B., Sjoholm N., Schou M., Pauli S., Mozley P.D., Stubbs J.B., Liow J.S., Sovago J., Gulyas B., Innis R., Halldin C. Whole-body biodistribution, radiation dosimetry estimates for the PET norepinephrine transporter probe (S,S)-[18F]FMeNER-D2 in non-human primates. Nucl Med Commun. 2005;26(8):695–700. [PubMed: 16000987]
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.
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.
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.
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.
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]
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]
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]
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]
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]
Iwata R., Pascali C., Bogni A., Furumoto S., Terasaki K., Yanai K. [18F]fluoromethyl triflate, a novel and reactive [18F]fluoromethylating agent: preparation and application to the on-column preparation of [18F]fluorocholine. Appl Radiat Isot. 2002;57(3):347–52. [PubMed: 12201141]
Schou M., Halldin C., Pike V.W., Mozley P.D., Dobson D., Innis R.B., Farde L., Hall H. Post-mortem human brain autoradiography of the norepinephrine transporter using (S,S)-[18F]FMeNER-D2. Eur Neuropsychopharmacol. 2005;15(5):517–20. [PubMed: 16139169]


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