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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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[11C]Carfentanil

[11C]CFN
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: February 14, 2013.

Chemical name:[11C]Carfentanilimage 24422969 in the ncbi pubchem database
Abbreviated name:[11C]CFN, [11C]CAR
Synonym:
Agent category:Compound
Target:Mu (μ) opioid receptor
Target category:Receptor
Method of detection:PET
Source of signal:11C
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Opioids such as morphine are commonly used analgesics in clinical practice. Three opioid receptors (mu, µ; delta, δ; and kappa, κ) that mediate opioid effects have been identified by molecular cloning: δ (enkephalin-preferring), κ (dynorphin-preferring), and µ (morphine and ß-endorphin-preferring) (1). Each type of opioid receptor consists of subtypes of receptors as suggested by pharmacological studies (2, 3). Their specificity and ubiquitous location are present in both the central and peripheral nervous system. The opioid receptors (G-protein coupled, resulting in decrease in adenylyl cyclase activity) play an important role in the regulation of analgesia, shock, appetite, thermoregulation, cardiovascular, mental and endocrine function (2-5). Although µ opioid receptors are the major receptor to mediate the analgesic effects of opioids, δ and κ receptors are also important in antinociception. Opioids have been found to protect cells from ischemia injury in the heart and brain via the δ receptors. On the other hand, κ antagonist prevents neurodegeneration.

The µ opioid receptors are localized predominately in the hypothalamus and thalamus, and the δ opioid receptors are localized predominately in the striatum, limbic system, and cerebral cortex (6, 7). The κ opioid receptors (κ1 and κ2 ) are the most abundant brain opioid receptors and are widely distributed in deeper layers of the neocortex (temporal, parietal, and frontal cortices), striatum, amygdala, and thalamus, with lower levels in the hippocampus, occipital cortex, and cerebellum (8-10). The µ opioid receptors have been implicated in several clinical brain disorders, including drug and alcohol abuses, epilepsy, and pain pathways (11-14).

Diprenorphine is a highly potent and nonselective opioid receptor antagonist with subnanomolar affinity (7). Diprenorphine was labeled as [6-O-methyl-11C]diprenorphine ([11C]DPN) (15, 16). [11C]DPN has been employed as a positron emission tomography (PET) agent for the non-invasive studies of opioid receptors in the brain of patients with pain, Huntington's disease, Parkinson’s disease, and epilepsy. Carfentanil (CFN) is a highly potent and selective µ opioid receptor agonist with subnanomolar affinity (Ki, 0.024 nM) (17). [11C]CFN is being developed as a PET agent for the non-invasive study of µ opioid receptors in the brain.

Synthesis

[PubMed]

Dannals et al. (18) reported synthesis of [11C]CFN by [11C]-O-methylation of the carboxylate precursor as sodium salt with [11C]methyl iodide. An average radiochemical yield was ~30% based on [11C]CO2 after HPLC purification with a total synthesis time of 30 min. An average specific activity was 42.6 GBq/μmol (1.15 Ci/μmol at end of synthesis) with a radiochemical purity of >97%.

Jewett et al. (19) reported a modified procedure for synthesis of [11C]CFN using an extraction disk instead of high-performance liquid chromatography (HPLC). The carboxylate precursor as the tetrabutylammonium salt was reacted at room temperature for 5 min with [11C]methyl triflate. [11C]CFN was trapped on a high performance extraction disk, and starting materials were selectively washed off. [11C]CFN was eluted with a small volume of ethanol. Radioactive contaminants were further removed by a small column of fibrous anion exchanger. The total synthesis time was ~10 min after purification. [11C]CFN was obtained in an averaged 15.6% radiochemical yield based on [11C]CO2 with a specific activity of 129.5 GBq/μmol (3.5 Ci/μmol) at end of synthesis. The radiochemical purity was >97%.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Titeler et al. (20) reported that [3H]CFN had a Kd of 0.08 ± 0.01 nM and a Bmax of 84 ± 3 fmol/mg tissue in vitro binding assays using human thalamic membranes. Cometta-Morini et al. (17) reported that CFN had Ki values of 0.024, 3.28, and 43.1 nM for the µ, δ, and κ opioid receptors, respectively.

Animal Studies

Rodents

[PubMed]

Saji et al. (21) demonstrated a high accumulation of [11C]CFN in the mouse brain with 3.73% injected dose/g (ID/g) at 5 min, 2.85%ID/g at 15 min, 2.13%ID/g at 30 min, and 1.28%ID/g at 60 min after injection (n = 4). The highest accumulation was in the thalamus, followed by the striatum, cortex, and cerebellum at all time points studied. Coinjection of [11C]CFN with naloxone (1 mg/kg) inhibited the accumulation by 73-74% in the thalamus and 62-82% in the striatum, whereas only marginal inhibition was observed in the cortex and cerebellum. Jewett et al. (22) reported that the hypothalamus exhibited a higher accumulation than the thalamus in the rats and mice. Regional binding potentials (BPs) were determined in the rat brain using bolus infusion of 96-178 MBq (2.6-4.8 mCi) of [11C]CFN with the cerebellum as the reference tissue (n = 4). The BP values were 4.81 ± 0.59, 3.30 ± 0.78, 3.06 ± 0.20, 2.21 ± 0.31, 1.97 ± 0.19, and 1.49 ± 0.26 for the hypothalamus, striatum, thalamus, cortex, hippocampus, and pons/medulla, respectively.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

Frost et al. (23, 24) reported [11C]CFN PET studies in human brain using reference methods or kinetic modeling. High concentrations of radioactivity were observed in the basal ganglia and thalamus, intermediate concentrations in the frontal and parietal cerebral cortex, and low concentrations in the cerebellum and occipital cortex. Naloxone pretreatment (1 mg/kg) inhibited ~90% of [11C]CFN binding in the caudate nucleus (K3/K4, from 3.4 to 0.26) and medial thalamus (K3/K4, from 1.8 to 0.16) for the period 30-60 min after tracer injection. Endres et al. (25) performed [11C]CFN PET studies with arterial blood sampling in six healthy male control subjects. Specific binding estimates obtained from reference-tissue methods were compared to those obtained with a more rigorous blood input modeling technique. It was determined that both a graphical method and a simplified reference tissue model were more accurate than the tissue-ratio method for quantification of [11C]CFN binding. The regional binding potentials obtained with all methods showed excellent correlation (r >0.97) with each other.

Mayberg et al. (26) reported that [11C]CFN binding (µ opioid receptors) in eleven patients with idiopathic epilepsy was increased in the temporal neocortex and decreased in the amygdala on the side of the epileptic focus. [11C]DPN binding (all opioid subtypes) was not significantly different among regions in the focus and nonfocus temporal lobes.

Newberg et al. (27) estimated the human dosimetry of [11C]CFN in 5 healthy subjects after injection of 280 MBq (7.6 mCi) of [11C]CFN. The organ receiving the highest radiation dose was the urinary bladder at 0.0365 mGy/MBq(0.135 rad/mCi). The effective dose was 4.6 μSv/MBq.

[11C]CFN has allowed studies of μ opioid receptors in patients with epilepsy, pains, lung carcinoma as well as drug, smoking and alcohol addictions [PubMed].

References

1.
Minami M., Satoh M. Molecular biology of the opioid receptors: structures, functions and distributions. Neurosci Res. 1995;23(2):121–45. [PubMed: 8532211]
2.
Waldhoer M., Bartlett S.E., Whistler J.L. Opioid receptors. Annu Rev Biochem. 2004;73:953–90. [PubMed: 15189164]
3.
Satoh M., Minami M. Molecular pharmacology of the opioid receptors. Pharmacol Ther. 1995;68(3):343–64. [PubMed: 8788562]
4.
Molina P.E. Opioids and opiates: analgesia with cardiovascular, haemodynamic and immune implications in critical illness. J Intern Med. 2006;259(2):138–54. [PubMed: 16420543]
5.
Barry U., Zuo Z. Opioids: old drugs for potential new applications. Curr Pharm Des. 2005;11(10):1343–50. [PubMed: 15853689]
6.
Chang K.J., Cooper B.R., Hazum E., Cuatrecasas P. Multiple opiate receptors: different regional distribution in the brain and differential binding of opiates and opioid peptides. Mol Pharmacol. 1979;16(1):91–104. [PubMed: 225656]
7.
Pfeiffer A., Pasi A., Mehraein P., Herz A. Opiate receptor binding sites in human brain. Brain Res. 1982;248(1):87–96. [PubMed: 6289997]
8.
Hiller J.M., Fan L.Q. Laminar distribution of the multiple opioid receptors in the human cerebral cortex. Neurochem Res. 1996;21(11):1333–45. [PubMed: 8947923]
9.
Peckys D., Landwehrmeyer G.B. Expression of mu, kappa, and delta opioid receptor messenger RNA in the human CNS: a 33P in situ hybridization study. Neuroscience. 1999;88(4):1093–135. [PubMed: 10336124]
10.
Simonin F., Gaveriaux-Ruff C., Befort K., Matthes H., Lannes B., Micheletti G., Mattei M.G., Charron G., Bloch B., Kieffer B. kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and expression pattern in the central nervous system. Proc Natl Acad Sci U S A. 1995;92(15):7006–10. [PMC free article: PMC41460] [PubMed: 7624359]
11.
Lever J.R. PET and SPECT imaging of the opioid system: receptors, radioligands and avenues for drug discovery and development. Curr Pharm Des. 2007;13(1):33–49. [PubMed: 17266587]
12.
Ravert H.T., Bencherif B., Madar I., Frost J.J. PET imaging of opioid receptors in pain: progress and new directions. Curr Pharm Des. 2004;10(7):759–68. [PubMed: 15032701]
13.
Sprenger T., Berthele A., Platzer S., Boecker H., Tolle T.R. What to learn from in vivo opioidergic brain imaging? Eur J Pain. 2005;9(2):117–21. [PubMed: 15737798]
14.
Ravert H.T., Mathews W.B., Musachio J.L., Scheffel U., Finley P., Dannals R.F. [11C]-methyl 4-[(3,4-dichlorophenyl)acetyl]-3-[(1-pyrrolidinyl)-methyl]-1- piperazinecarboxylate ([11C]GR89696): synthesis and in vivo binding to kappa opiate receptors. Nucl Med Biol. 1999;26(7):737–41. [PubMed: 10628552]
15.
Lever J.R., Dannals R.F., Wilson A.A., Ravert H.T., Wagner H.N. Jr. Synthesis of carbon-11 labeled diprenorphine: a radioligand for positron emission tomographic studies of opiate receptors. Tetrahedron Letters. 1987;28(35):4015–4018.
16.
Luthra S.K., Brady F., Turton D.R., Brown D.J., Dowsett K., Waters S.L., Jones A.K., Mathews R.W., Crowder J.C. Automated radiosyntheses of [6-O-methyl-11C]diprenorphine and [6-O-methyl-11C]buprenorphine from 3-O-trityl protected precursors. Appl Radiat Isot. 1994;45(8):857–873.
17.
Cometta-Morini C., Maguire P.A., Loew G.H. Molecular determinants of mu receptor recognition for the fentanyl class of compounds. Mol Pharmacol. 1992;41(1):185–96. [PubMed: 1310142]
18.
Dannals R.F., Ravert H.T., Frost J.J., Wilson A.A., Burns H.D., Wagner H.N. Jr. Radiosynthesis of an opiate receptor binding radiotracer: [11C]carfentanil. Int J Appl Radiat Isot. 1985;36(4):303–6. [PubMed: 2991142]
19.
Jewett D.M. A simple synthesis of [11C]carfentanil using an extraction disk instead of HPLC. Nucl Med Biol. 2001;28(6):733–4. [PubMed: 11518656]
20.
Titeler M., Lyon R.A., Kuhar M.J., Frost J.F., Dannals R.F., Leonhardt S., Bullock A., Rydelek L.T., Price D.L., Struble R.G. Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain. Eur J Pharmacol. 1989;167(2):221–8. [PubMed: 2556284]
21.
Saji H., Tsutsumi D., Magata Y., Iida Y., Konishi J., Yokoyama A. Preparation and biodistribution in mice of [11C]carfentanil: a radiopharmaceutical for studying brain mu-opioid receptors by positron emission tomography. Ann Nucl Med. 1992;6(1):63–7. [PubMed: 1325823]
22.
Jewett D.M., Kilbourn M.R. In vivo evaluation of new carfentanil-based radioligands for the mu opiate receptor. Nucl Med Biol. 2004;31(3):321–5. [PubMed: 15028244]
23.
Frost J.J., Douglass K.H., Mayberg H.S., Dannals R.F., Links J.M., Wilson A.A., Ravert H.T., Crozier W.C., Wagner H.N. Jr. Multicompartmental analysis of [11C]-carfentanil binding to opiate receptors in humans measured by positron emission tomography. J Cereb Blood Flow Metab. 1989;9(3):398–409. [PubMed: 2541148]
24.
Frost J.J., Wagner H.N. Jr, Dannals R.F., Ravert H.T., Links J.M., Wilson A.A., Burns H.D., Wong D.F., McPherson R.W., Rosenbaum A.E. et al. Imaging opiate receptors in the human brain by positron tomography. J Comput Assist Tomogr. 1985;9(2):231–6. [PubMed: 2982931]
25.
Endres C.J., Bencherif B., Hilton J., Madar I., Frost J.J. Quantification of brain mu-opioid receptors with [11C]carfentanil: reference-tissue methods. Nucl Med Biol. 2003;30(2):177–86. [PubMed: 12623117]
26.
Mayberg H.S., Sadzot B., Meltzer C.C., Fisher R.S., Lesser R.P., Dannals R.F., Lever J.R., Wilson A.A., Ravert H.T., Wagner H.N. Jr. et al. Quantification of mu and non-mu opiate receptors in temporal lobe epilepsy using positron emission tomography. Ann Neurol. 1991;30(1):3–11. [PubMed: 1656846]
27.
Newberg A.B., Ray R., Scheuermann J., Wintering N., Saffer J., Schmitz A., Freifelder R., Karp J., Lerman C., Divgi C. Dosimetry of 11C-carfentanil, a micro-opioid receptor imaging agent. Nucl Med Commun. 2009;30(4):314–8. [PubMed: 19242386]

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