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Open Access 01-12-2019 | Positron Emission Tomography | Original research

Potential for imaging the high-affinity state of the 5-HT_1B receptor: a comparison of three PET radioligands with differing intrinsic activity

Authors: Anton Lindberg, Ryosuke Arakawa, Tsuyoshi Nogami, Sangram Nag, Magnus Schou, Charles S. Elmore, Lars Farde, Victor W. Pike, Christer Halldin

Published in: EJNMMI Research | Issue 1/2019

Abstract

Background

Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT_1B receptors. The 5-HT_1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT_1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity ¹¹C-labeled 5-HT_1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release.

Results

A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [¹¹C]3. The most antagonistic radioligand showed the lowest reduction in specific binding.

Conclusions

Three 5-HT_1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT_1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

Moret C, Briley M. The possible role of 5-HT1B/D receptors in psychiatric disorders and their potential as a target for therapy. Eur J Pharmacol. 2000;404:1–12. https://doi.org/10.1016/s0014-2999(00)00581-1.CrossRefPubMed

Ruf BM, Bhagwagar Z. The 5-HT1B receptor: a novel target for the pathophysiology of depression. Curr Drug Targets. 2009;10:1118–38.CrossRef

Hannon J, Hoyer D. Molecular biology of 5-HT receptors. Behav Brain Res. 2008;195:198–213. https://doi.org/10.1016/j.bbr.2008.03.020.CrossRefPubMed

Kobilka BK. G protein coupled receptor structure and activation. Biochimica Et Biophysica Acta-Biomembranes. 2007;1768:794–807. https://doi.org/10.1016/j.bbamem.2006.10.021.CrossRef

Clawges HM, Depree KM, Parker EM, Graber SG. Human 5-HT1 receptor subtypes exhibit distinct G protein coupling behaviors in membranes from Sf9 cells. Biochemistry. 1997;36:12930–8. https://doi.org/10.1021/bi970112b.CrossRefPubMed

Barnes NM, Sharp T. A review of central 5-HT receptors and their function. Neuropharmacology. 1999;38:1083–152. https://doi.org/10.1016/s0028-3908(99)00010-6.CrossRefPubMed

Kenakin T. Ligand-selective receptor conformations revisited: the promise and the problem. Trends Pharmacol Sci. 2003;24:346–54. https://doi.org/10.1016/s0165-6147(03)00167-6.CrossRefPubMed

Garcia-Nafria J, Nehme R, Edwards PC, Tate CG. Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric G(o). Nature. 2018;558:620. https://doi.org/10.1038/s41586-018-0241-9.CrossRefPubMedPubMedCentral

Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, Mylecharane EJ, et al. International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev. 1994;46:157–203.PubMed

10.

Brys R, Josson K, Castelli MP, Jurzak M, Lijnen P, Gommeren W, et al. Reconstitution of the human 5-HT1D receptor-G-protein coupling: evidence for constitutive activity and multiple receptor conformations. Mol Pharmacol. 2000;57:1132–41.PubMed

11.

Yin WC, Zhou XE, Yang DH, de Waal PW, Wang MT, Dai AT, et al. Crystal structure of the human 5-HT1B serotonin receptor bound to an inverse agonist. Cell Discov. 2018;4. https://doi.org/10.1038/s41421-018-0009-2.

12.

Wang C, Jiang Y, Ma JM, Wu HX, Wacker D, Katritch V, et al. Structural basis for molecular recognition at serotonin receptors. Science. 2013;340:610–4. https://doi.org/10.1126/science.1232807.CrossRefPubMedPubMedCentral

13.

Seneca N, Finnema SJ, Farde L, Gulyas B, Wikstrom HV, Halldin C, et al. Effect of amphetamine on dopamine D2 receptor binding in nonhuman primate brain: a comparison of the agonist radioligand (11C) MNPA and antagonist C-11 raclopride. Synapse. 2006;59:260–9. https://doi.org/10.1002/syn.20238.CrossRefPubMed

14.

Shalgunov V, van Waarde A, Booij J, Michel MC, Dierckx RAJO, Elsinga PH. Hunting for the high-affinity state of G-protein-coupled receptors with agonist tracers: theoretical and practical considerations for positron emission tomography imaging. Med Res Rev. 2018. https://doi.org/10.1002/med.21552.

15.

Lindberg A, Nag S, Schou M, Takano A, Matsumoto J, Amini N, et al. [(11)C]AZ10419096 - a full antagonist PET radioligand for imaging brain 5-HT1B receptors. Nucl Med Biol. 2017;54:34–40. https://doi.org/10.1016/j.nucmedbio.2017.07.007.CrossRefPubMed

16.

Finnema SJ, Varrone A, Hwang TJ, Gulyas B, Pierson ME, Halldin C, et al. Fenfluramine-induced serotonin release decreases C-11 AZ10419369 binding to 5-HT1B-receptors in the primate brain. Synapse. 2010;64:573–7. https://doi.org/10.1002/syn.20780.CrossRefPubMed

17.

Lindberg A, Lu S, Nag S, Schou M, Liow J-S, Zoghbi SS, et al. Synthesis and evaluation of two new candidate high-affinity full agonist PET radioligands for imaging 5-HT1B receptors. Nucl Med Biol. 2019;70:1–13. https://doi.org/10.1016/j.nucmedbio.2019.01.005.CrossRefPubMedPubMedCentral

18.

Andersson JD, Pierson ME, Finnema SJ, Gulyas B, Heys R, Elmore CS, et al. Development of a PET radioligand for the central 5-HT1B receptor: radiosynthesis and characterization in cynomolgus monkeys of eight radiolabeled compounds. Nucl Med Biol. 2011;38:261–72. https://doi.org/10.1016/j.nucmedbio.2010.08.006.CrossRefPubMed

19.

Lindberg A, Lu S, Liow J, Zoghbi S, Frankland MP, Gladding RL, et al. New candidate high-affinity full agonist PET radioligands for imaging 5-HT(1B)receptors have very low brain uptake and no signal. Eur J Nucl Med Mol Imaging. 2018;45:S643–S4.

20.

Pierson ME, Andersson J, Nyberg S, McCarthy DJ, Finnema SJ, Varnas K, et al. (11)C AZ10419369: a selective 5-HT(1B) receptor radioligand suitable for positron emission tomography (PET). Characterization in the primate brain. Neuroimage. 2008;41:1075–85. https://doi.org/10.1016/j.neuroimage.2008.02.063.CrossRefPubMed

21.

Karlsson P, Farde L, Halldin C, Swahn CG, Sedvall G, Foged C, et al. PET examination OF C-11 NNC-687 and C-11 NNC-756 as new radioligands for the D-1-dopamine receptor. Psychopharmacology. 1993;113:149–56. https://doi.org/10.1007/bf02245691.CrossRefPubMed

22.

Varrone A, Sjoholm N, Eriksson L, Gulyas B, Halldin C, Farde L. Advancement in PET quantification using 3D-OP-OSEM point spread function reconstruction with the HRRT. Eur J Nucl Med Mol Imaging. 2009;36:1639–50. https://doi.org/10.1007/s00259-009-1156-3.CrossRefPubMed

23.

Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage. 1996;4:153–8. https://doi.org/10.1006/nimg.1996.0066.CrossRefPubMed

24.

Varnas K, Hall H, Bonaventure P, Sedvall G. Autoradiographic mapping of 5-HT(1B) and 5-HT(1D) receptors in the post mortem human brain using [(3)H]GR 125743. Brain Res. 2001;915:47–57.CrossRef

25.

Yang K-C, Stepanov V, Martinsson S, Ettrup A, Takano A, Knudsen GM, et al. Fenfluramine reduces C-11 Cimbi-36 binding to the 5-HT2A receptor in the nonhuman primate brain. Int J Neuropsychopharmacol. 2017;20:683–91. https://doi.org/10.1093/ijnp/pyx051.CrossRefPubMedPubMedCentral

26.

De Haes JIU, Harada N, Elsinga PH, Maguire RP, Tsukada H. Effect of fenfluramine-induced increases in serotonin release on F-18 MPPF binding: a continuous infusion PET study in conscious monkeys. Synapse. 2006;59:18–26. https://doi.org/10.1002/syn.20209.CrossRef

Title: Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity
Authors: Anton Lindberg
Ryosuke Arakawa
Tsuyoshi Nogami
Sangram Nag
Magnus Schou
Charles S. Elmore
Lars Farde
Victor W. Pike
Christer Halldin
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Keyword: Positron Emission Tomography
Published in: EJNMMI Research / Issue 1/2019
Electronic ISSN: 2191-219X
DOI: https://doi.org/10.1186/s13550-019-0570-1

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Potential for imaging the high-affinity state of the 5-HT_1B receptor: a comparison of three PET radioligands with differing intrinsic activity

Abstract

Background

Results

Conclusions

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Springer Medicine

Abstract

Background

Results

Conclusions

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