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6-O-(2-[18F]Fluoroethyl)-6-O-Desmethyl-Diprenorphine ([18F]FE-DPN) Preferentially Binds to Mu Opioid Receptors In Vivo



6-O-(2-[18F]Fluoroethyl)-6-O-desmethyl-diprenorphine ([18F]FE-DPN) is regarded as a non-selective opioid receptor radiotracer.


Here, we report the first characterization of [18F]FE-DPN synthesized from the novel precursor, 6-O-(2-tosyloxyethoxy)-6-O-desmethyl-3-O-trityl-diprenorphine (TE-TDDPN), using a one-pot, two-step nucleophilic radiosynthesis to image opioid receptors in rats and mice using positron emission tomography.


We also show that [18F]FE-DPN and [3H]DPN exhibit negligible brain uptake in mu opioid receptor (MOR) knockout mice.


Taken together with prior findings, our results suggest that [18F]FE-DPN and [3H]DPN preferentially bind to MOR in rodents in vivo.

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  1. Wester HJ, Willoch F, Tolle TR et al (2000) 6-O-(2-[18F]fluoroethyl)-6-O-desmethyldiprenorphine ([18F]DPN): synthesis, biologic evaluation, and comparison with [11C]DPN in humans. J Nucl Med 41:1279–1286

    CAS  PubMed  Google Scholar 

  2. Mueller C, Klega A, Buchholz HG et al (2010) Basal opioid receptor binding is associated with differences in sensory perception in healthy human subjects: a [18F]diprenorphine PET study. Neuroimage 49:731–737

    Article  Google Scholar 

  3. Thompson SJ, Pitcher MH, Stone LS et al (2018) Chronic neuropathic pain reduces opioid receptor availability with associated anhedonia in rat. Pain 159:1856–1866

    CAS  Article  Google Scholar 

  4. Raynor K, Kong H, Chen Y et al (1994) Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors. Mol Pharmacol 45:330–334

    CAS  PubMed  Google Scholar 

  5. Chang KJ, Hazum E, Cuatrecasas P (1980) Possible role of distinct morphine and enkephalin receptors in mediating actins of benzomorphan drugs (putative kappa and sigma agonists). Proc Natl Acad Sci U S A 77:4469–4473

    CAS  Article  Google Scholar 

  6. Chang KJ, Hazum E, Cuatrecasas P (1981) Novel opiate binding sites selective for benzomorphan drugs. Proc Natl Acad Sci U S A 78:4141–4145

    CAS  Article  Google Scholar 

  7. Henriksen G, Willoch F, Talbot PS, Wester HJ (2006) Recent development and potential use of mu- and kappa-opioid receptor ligands in positron emission tomography studies. Drug Develop Res 67:890–904

    CAS  Article  Google Scholar 

  8. Schoultz BW, Hjornevik T, Reed BJ et al (2014) Synthesis and evaluation of three structurally related (1)(8)F-labeled orvinols of different intrinsic activities: 6-O-[(1)(8)F]fluoroethyl-diprenorphine ([(1)(8)F]FDPN), 6-O-[(1)(8)F]fluoroethyl-buprenorphine ([(1)(8)F]FBPN), and 6-O-[(1)(8)F]fluoroethyl-phenethyl-orvinol ([(1)(8)F]FPEO). J Med Chem 57:5464–5469

    CAS  Article  Google Scholar 

  9. Frost JJ, Dannals RF, Duelfer T et al (1984) In vivo studies of opiate receptors. Ann Neurol 15(Suppl):S85-92

    Article  Google Scholar 

  10. Zeeberg BR (1999) Pharmacokinetic computer simulations of the relationship between in vivo and in vitro neuroreceptor subtype selectivity of radioligands. Nucl Med Biol 26:803–809

    CAS  Article  Google Scholar 

  11. Frost JJ, Smith AC, Wagner HN Jr (1986) 3H-diprenorphine is selective for mu opiate receptors in vivo. Life Sci 38:1597–1606

    CAS  Article  Google Scholar 

  12. Atweh SF, Kuhar MJ (1977) Autoradiographic localization of opiate receptors in rat brain III. The telencephalon Brain Res 134:393–405

    CAS  Article  Google Scholar 

  13. Marton J, Cumming P, Bauer B, Henriksen G (2021) A new precursor for the radiosynthesis of 6-O-(2-[(18) F]fluoroethyl)-6-O-desmethyl-diprenorphine ([F-18]FE-DPN) by nucleophilic radiofluorination. Lett Org Chem 18:344–352

    CAS  Article  Google Scholar 

  14. Bonaventura J, Lam S, Carlton M et al (2021) Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability. Mol Psychiatry 26:6704–6722

    CAS  Article  Google Scholar 

  15. Ichise M, Ballinger JR, Golan H et al (1996) Noninvasive quantification of dopamine D2 receptors with iodine-123-IBF SPECT. J Nucl Med 37:513–520

    CAS  PubMed  Google Scholar 

  16. Kitchen I, Slowe SJ, Matthes HW, Kieffer B (1997) Quantitative autoradiographic mapping of mu-, delta- and kappa-opioid receptors in knockout mice lacking the mu-opioid receptor gene. Brain Res 778:73–88

    CAS  Article  Google Scholar 

  17. Cumming P, Marton J, Lilius TO, Olberg DE, Rominger A (2019) A survey of molecular imaging of opioid receptors. Molecules 24:4190.

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This work was supported by the NIDA Intramural Research Program (ZIA000069, MM) and by Grants RYC-2019-027371-I (JB) funded by MCIN/AEI/1013039/501100011033 and by “ESF Investing in your future,” Plan Nacional Sobre Drogas 2021I070 (JB) funded by the Spanish Ministerio de Sanidad, and (EB024495, MGP) funded by NIBIB.

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Authors and Affiliations



Designed and performed experiments, analyzed data, and wrote the manuscript: MRL, MM. Designed experiments, analyzed data, and wrote the manuscript: JB. Designed and performed experiments: ENV, JLG, DH. Performed experiments: RCB. Contributed resources and reagents: MJ, GH, RFD, MGP, CAZ. All coauthors reviewed the manuscript and provided comments.

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Correspondence to Michael Michaelides.

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Conflict of Interest

MM has received research funding from AstraZeneca, Redpin Therapeutics, and Attune Neurosciences. CAZ is listed as a coinventor on a patent for the use of ketamine in major depression and suicidal ideation. CAZ is listed as a coinventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain. CAZ is listed as coinventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. CAZ has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors declare no conflicts of interest.

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Levinstein, M.R., Ventriglia, E.N., Gomez, J.L. et al. 6-O-(2-[18F]Fluoroethyl)-6-O-Desmethyl-Diprenorphine ([18F]FE-DPN) Preferentially Binds to Mu Opioid Receptors In Vivo. Mol Imaging Biol (2022).

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Key words

  • Diprenorphine
  • PET
  • Opioid
  • In vivo