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

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Abstract

Purpose

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

Procedure

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.

Results

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

Conclusions

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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References

  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  PubMed  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

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  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

    Article  CAS  PubMed  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  PubMed  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

    Article  CAS  PubMed  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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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

    Article  CAS  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

    Article  CAS  PubMed  PubMed Central  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

    Article  CAS  PubMed  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.

Download references

Funding

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

  1. Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute On Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA

    Marjorie R. Levinstein, Emilya N. Ventriglia, Juan L. Gomez, Reece C. Budinich & Michael Michaelides

  2. ABX Advanced Biochemical Compounds Biomedizinische Forschungsreagenzien GmbH, Heinrich-Glaeser-Strasse 10-14, 01454, Radeberg, Germany

    János Marton

  3. Institute of Basic Medical Sciences, University of Oslo, Blindern, P. O. Box 1105, N-0317, Oslo, Norway

    Gjermund Henriksen

  4. Norwegian Medical Cyclotron Centre Ltd, Sognsvannsveien 20, N-0372, Oslo, Norway

    Gjermund Henriksen

  5. Institute of Physics, University of Oslo, Sem Sælands vei 24, N-0371, Oslo, Norway

    Gjermund Henriksen

  6. Department of Radiology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA

    Daniel P. Holt, Robert F. Dannals & Martin G. Pomper

  7. Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, Bethesda, MD, 20892, USA

    Carlos A. Zarate Jr

  8. Departament de Patologia I Terapèutica Experimental, Institut de Neurociències, Universitat de Barcelona, L’Hospitalet de Llobregat, Catalonia, Spain

    Jordi Bonaventura

  9. Neuropharmacology and Pain Group, Neuroscience Program, Institut d’Investigació Biomèdica de Bellvitge, IDIBELL, 08907, L’Hospitalet de Llobregat, Catalonia, Spain

    Jordi Bonaventura

  10. Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA

    Michael Michaelides

Authors
  1. Marjorie R. Levinstein
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  2. Emilya N. Ventriglia
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  3. Juan L. Gomez
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  4. Reece C. Budinich
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  5. János Marton
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  6. Gjermund Henriksen
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  7. Daniel P. Holt
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  8. Robert F. Dannals
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  9. Martin G. Pomper
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  10. Carlos A. Zarate Jr
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  11. Jordi Bonaventura
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  12. Michael Michaelides
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Contributions

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.

Corresponding author

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 25, 384–390 (2023). https://doi.org/10.1007/s11307-022-01767-5

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  • DOI: https://doi.org/10.1007/s11307-022-01767-5

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