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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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2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine

[11C]CIMBI-5
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: March 23, 2011.

Chemical name:2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamineimage 113234400 in the ncbi pubchem database
Abbreviated name:[11C]CIMBI-5
Synonym:
Agent category:Compound
Target:5-HT2A serotonin receptor
Target category:Receptor
Method of detection:Positron emission tomography (PET)
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Non-primate non-rodent mammals
Click on the above structure for additional information in PubChem.

Background

[P ubMed]

Serotonin (5-hydroxytryptamine, 5-HT) has diverse physiological roles as a neurotransmitter in the central nervous system (1). It is involved in the regulation and modulation of sleep, affective and personality behaviors, and pain. It also is a regulator of smooth muscle function and platelet aggregation. The brain cortical 5-HT system has been implicated in several neuropsychiatric disorders, including major depression, anxiety, obsessive-compulsive disorder, and schizophrenia (2, 3). The effects of 5-HT are mediated by as many as seven classes of receptor populations (5-HT1 to 5-HT7), many of which include several subtypes (4). There are three receptor subtypes within the G-protein–coupled 5-HT2 receptor family: 5-HT2A, 5-HT2B, and 5-HT2C.

5-HT2A receptors are abundantly present in the cerebral cortex, basal forebrain, hippocampus, amygdala, dorsal thalamus, hypothalamus, superior colliculus, substantia nigra, pedunculopontine nucleus, legmental area, and myelencephalon (5). 5-HT2A receptors are involved in mediation of normal and psychotic states, working memory, regulation of GABAergic and cholinergic neuronal cells, sleep, peripheral pain, and cardiovascular functions. 5-HT2B receptors are found mainly in several peripheral tissues, such as the stomach, intestine, pulmonary smooth muscle, and myocardium. In the brain, 5-HT2B receptors are found in discrete nuclei of the cerebellum, lateral septum, dorsal hypothalamus, dorsal raphe, and amygdala. 5-HT2C receptors are found in the choroid plexus, substantia nigra, globus pallidus, and ventromedial thalamus. 5-HT2A receptors are implicated in several psychiatric disorders, such as schizophrenia, depression, and obsessive-compulsive disorder. Thus, there is a need for selective ligands to investigate the pharmacological role of 5-HT2A receptors.

There have been several studies to develop specific 5-HT2A radioligands, such as [11C]ketanserin (6), [18F]spiperone (7), [11C]methylspiperone ([11C]NMSP), and [18F]setoperone [PubMed], for positron emission tomography (8) imaging. However, none of these ligands has proven to be specific for 5-HT2A receptors because these compounds also bind to other receptors, such as dopamine receptors and the 5-HT1 receptor subtypes. Altanserin, a fluorobenzoyl derivative related to ketanserin, was reported to be a potent antagonist of 5-HT2A receptors with >100-fold selectivity over D2/3 receptors, 5-HT1A, 5-HT6, and 5-HT7 (9, 10). This led to the development of 3-{2-[4-(4-[18F]fluorobenzoyl)-1-piperidyl]ethyl}-2-sulfanyl-3H-quinazolin-4-one ([18F]altanserin) as a useful tool for 5-HT2A receptor PET imaging in vivo (11). 5-HT2A antagonists bind to the total pool of receptors, whereas 5-HT2A agonists bind only to the high-affinity functional state of the receptor but may be more important in disease states because the high affinity sites are the ones that transmit the intracellular signals. Furthermore, 2-(4-Iodo-2,5-dimethoxyphenyl)-N-(2-[11C]methoxybenzyl)ethanamine ([11C]CIMBI-5), a potent and selective 5-HT2A agonist, has been developed as a tool for studying 5-HT2A agonist binding in the brain (12).

Synthesis

[PubMed]

Ettrup et al. (12) reported a two-step reaction synthesis of [11C]CIMBI-5 by reacting [11C]methyl triflate with the Boc-protected precursor, followed by acid hydrolysis. [11C]CIMBI-5 was purified with column chromatography. Specific activities were 64–355 GBq/μmol (1.7–9.6 Ci/μmol) at the end of synthesis with a radiochemical purity >97%. The total synthesis time was 40–50 min. The lipophilicity (cLogD7.4) was calculated to be 3.21. The radiochemical yield was not reported.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

CIMBI-5 has been reported to have high binding affinity for the 5-HT2A receptor. Ettrup et al. (12) reported Ki values of 2.2, 2.3, 7.0, 58, and 85 nM for 5-HT2A, 5-HT2B, 5-HT2C, 5-HT6, and 5-HT1A receptors, respectively. CIMBI-5 exhibited at least a 30-fold lower affinity for a variety of receptors. CIMBI-5 was found to induce phosphoinositide hydrolysis in GF62 cells overexpressing the 5-HT2A receptor with an EC50 of 1.02 nM. These data demonstrate that CIMBI-5 is a specific and selective 5-HT2A agonist.

Animal Studies

Rodents

[PubMed]

Ex vivo biodistribution studies in rats (n = 2–4/group) showed a moderate accumulation of radioactivity in the frontal cortex at 5, 15, 30, 45, and 60 min after injection of 4 MBq/kg (0.11 mCi/kg) [11C]CIMBI-5 (12). Accumulation of the tracer in the frontal cortex peaked at 30 min (specific binding ratio (SBR, (region of interest – cerebellum)/cerebellum) = 0.77, using the cerebellum as a reference), followed by a slow decrease of radioactivity to an SBR of 0.5 at 60 min. The accumulation in the cerebellum was lower than in the frontal cortex and paralleled the plasma time–activity curve. Pretreatment with 1 mg/kg ketanserin 45 min before [11C]CIMBI-5 injection reduced the SBR to 0.076 at 30 min after injection (P < 0.0001).

Other Non-Primate Mammals

[PubMed]

Ettrup et al. (12) performed PET imaging studies in six female Danish Landrace pigs with injection of ~238 MBq (6.4 mCi) [11C]CIMBI-5. [11C]CIMBI-5 exhibited high cortical accumulation, moderate accumulation in the striatum and thalamus, and low accumulation in the cerebellum. The standard uptake values at 80 min after injection were 0.8 g/ml and 0.5 g/ml for the frontal cortex and cerebellum, respectively. Pretreatment with ketanserin reduced the standard uptake value at the same time point to 0.5 g/ml in the frontal cortex with little effect on the cerebellum. Kinetic modeling with the simplified reference tissue model (SRTM) showed that the cortical nondisplaceable binding potential (BPND) value was 0.46 ± 0.11 (n = 5); this value decreased to 0.11 ± 0.06 (n = 3) with ketanserin pretreatment. One-tissue (BPND = 0.57) and two-tissue (BPND = 0.61) compartment models showed similar baseline cortical BPND values. As a comparison, [18F]altanserin showed a cortical SRTM BPND value of 0.47 ± 0.10. [11C]CIMBI-5 was >90% intact in the frontal cortex and cerebellum at 25 min after injection and ~18% intact in the plasma with two less lipophilic metabolites.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

References

1.
Lucki I. The spectrum of behaviors influenced by serotonin. Biol Psychiatry. 1998;44(3):151–62. [PubMed: 9693387]
2.
Fletcher A., Cliffe I.A., Dourish C.T. Silent 5-HT1A receptor antagonists: utility as research tools and therapeutic agents. Trends Pharmacol Sci. 1993;14(12):41–8. [PubMed: 8122313]
3.
Hoyer D., Clarke D.E., Fozard J.R., Hartig P.R., Martin G.R., Mylecharane E.J., Saxena P.R., Humphrey P.P. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994;46(2):157–203. [PubMed: 7938165]
4.
Lanfumey L., Hamon M. 5-HT1 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3(1):1–10. [PubMed: 14965240]
5.
Leysen J.E. 5-HT2 receptors. Curr Drug Targets CNS Neurol Disord. 2004;3(1):11–26. [PubMed: 14965241]
6.
Dewey S.L., Smith G.S., Logan J., Brodie J.D. Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates. Neuropsychopharmacology. 1993;8(4):371–6. [PubMed: 8512623]
7.
Shiue C.Y., Fowler J.S., Wolf A.P., Watanabe M., Arnett C.D. Syntheses and specific activity determinations of no-carrier-added (NCA) F-18-labeled butyrophenone neuroleptics--benperidol, haloperidol, spiroperidol, and pipamperone. J Nucl Med. 1985;26(2):181–6. [PubMed: 2857191]
8.
Gao X., Yang L., Petros J.A., Marshall F.F., Simons J.W., Nie S. In vivo molecular and cellular imaging with quantum dots. Curr Opin Biotechnol. 2005;16(1):63–72. [PubMed: 15722017]
9.
Leysen, J., Use of 5-HT receptor agonists and antagonists for the characterization of their respective recptor sites. In: A.B. Boulton, G.B. Baker and A.V. Jurio Editors, Drugs as Tools in Neurotransmitter Research. Neuromethods The Human Press, Clifton, NJ 1989: p. 299-341.
10.
Tan P.Z., Baldwin R.M., Van Dyck C.H., Al-Tikriti M., Roth B., Khan N., Charney D.S., Innis R.B. Characterization of radioactive metabolites of 5-HT2A receptor PET ligand [18F]altanserin in human and rodent. Nucl Med Biol. 1999;26(6):601–8. [PubMed: 10587097]
11.
Lemaire C., Cantineau R., Guillaume M., Plenevaux A., Christiaens L. Fluorine-18-altanserin: a radioligand for the study of serotonin receptors with PET: radiolabeling and in vivo biologic behavior in rats. J Nucl Med. 1991;32(12):2266–72. [PubMed: 1744713]
12.
Ettrup A., Palner M., Gillings N., Santini M.A., Hansen M., Kornum B.R., Rasmussen L.K., Nagren K., Madsen J., Begtrup M., Knudsen G.M. Radiosynthesis and evaluation of 11C-CIMBI-5 as a 5-HT2A receptor agonist radioligand for PET. J Nucl Med. 2010;51(11):1763–70. [PubMed: 20956470]
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