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EC50 images, a novel endpoint from PET target occupancy studies, reveal spatial variation in apparent drug affinity

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

We recently introduced voxel-level images of drug occupancy from PET via our “Lassen plot filter.” Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an “EC50 image” from human data to evaluate this hypothesis.

Methods

Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50.

Results

As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision.

Conclusion

Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials.

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Data availability

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Gunn RN, Rabiner EA. Imaging in central nervous system drug discovery. Semin Nucl Med. 2017;47:89–98. https://doi.org/10.1053/j.semnuclmed.2016.09.001.

    Article  PubMed  Google Scholar 

  2. Ashworth S, Berges A, Rabiner EA, Wilson AA, Comley RA, Lai RYK, et al. Unexpectedly high affinity of a novel histamine H3 receptor antagonist, GSK239512, in vivo in human brain, determined using PET. Br J Pharmacol. 2014;171:1241–9. https://doi.org/10.1111/bph.12505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lim KS, Kwon JS, Jang I-J, Jeong JM, Lee JS, Kim HW, et al. Modeling of brain D2 receptor occupancy-plasma concentration relationships with a novel antipsychotic, YKP1358, using serial PET scans in healthy volunteers. Clin Pharmacol Ther. 2007;81:252–8. https://doi.org/10.1038/sj.clpt.6100049.

    Article  CAS  PubMed  Google Scholar 

  4. Takano A, Halldin C, Farde L. SERT and NET occupancy by venlafaxine and milnacipran in nonhuman primates: a PET study. Psychopharmacology. 2013;226:147–53. https://doi.org/10.1007/s00213-012-2901-z.

    Article  CAS  PubMed  Google Scholar 

  5. Di Ciano P, Mansouri E, Tong J, Wilson AA, Houle S, Boileau I, et al. Occupancy of dopamine D2 and D3 receptors by a novel D3 partial agonist BP1.4979: a [11C]-(+)-PHNO PET study in humans. Neuropsychopharmacology. 2019;44:1284–90. https://doi.org/10.1038/s41386-018-0285-4.

    Article  CAS  PubMed  Google Scholar 

  6. Jucaite A, Takano A, Boström E, Jostell K-G, Stenkrona P, Halldin C, et al. AZD5213: a novel histamine H3 receptor antagonist permitting high daytime and low nocturnal H3 receptor occupancy, a PET study in human subjects. Int J Neuropsychopharmacol. 2013;16:1231–9. https://doi.org/10.1017/S1461145712001411.

    Article  CAS  PubMed  Google Scholar 

  7. Hirvonen J, Kailajärvi M, Haltia T, Koskimies S, Någren K, Virsu P, et al. Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301. Clin Pharmacol Ther. 2009;85:506–12. https://doi.org/10.1038/clpt.2008.241.

    Article  CAS  PubMed  Google Scholar 

  8. Rusjan P, Sabioni P, Di Ciano P, Mansouri E, Boileau I, Laveillé A, et al. Exploring occupancy of the histamine H3 receptor by pitolisant in humans using PET. Br J Pharmacol. 2020;177:3464–72. https://doi.org/10.1111/bph.15067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stenkrona P, Halldin C, Lundberg J. 5-HTT and 5-HT1A receptor occupancy of the novel substance vortioxetine (Lu AA21004). A PET study in control subjects. European Neuropsychopharmacology. 2013;23:1190–8. https://doi.org/10.1016/j.euroneuro.2013.01.002.

    Article  CAS  PubMed  Google Scholar 

  10. Lassen NA, Bartenstein PA, Lammertsma AA, Prevett MC, Turton DR, Luthra SK, et al. Benzodiazepine receptor quantification in vivo in humans using [11C]flumazenil and PET: application of the steady-state principle. J Cereb Blood Flow Metab. 1995;15:152–65. https://doi.org/10.1038/jcbfm.1995.17.

    Article  CAS  PubMed  Google Scholar 

  11. Salahudeen MS, Nishtala PS. An overview of pharmacodynamic modelling, ligand-binding approach and its application in clinical practice. Saudi Pharm J. 2017;25:165–75. https://doi.org/10.1016/j.jsps.2016.07.002.

    Article  PubMed  Google Scholar 

  12. Takano A, Varrone A, Gulyás B, Salvadori P, Gee A, Windhorst A, et al. Guidelines to PET measurements of the target occupancy in the brain for drug development. Eur J Nucl Med Mol Imaging. 2016;43:2255–62. https://doi.org/10.1007/s00259-016-3476-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Laat B, Morris ED. A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images. Journal of Cerebral Blood Flow & Metabolism. 2020:0271678X20950486. doi:https://doi.org/10.1177/0271678X20950486.

  14. Myers JFM, Comley RA, Gunn RN. Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans. J Cereb Blood Flow Metab. 2016;37:2137–48. https://doi.org/10.1177/0271678X16661339.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Nickolls SA, Gurrell R, van Amerongen G, Kammonen J, Cao L, Brown AR, et al. Pharmacology in translation: the preclinical and early clinical profile of the novel alpha2/3 functionally selective GABAA receptor positive allosteric modulator PF-06372865. Br J Pharmacol. 2018;175:708–25. https://doi.org/10.1111/bph.14119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hurvich CM, Tsai C-L. Regression and time series model selection in small samples. Biometrika. 1989;76:297–307. https://doi.org/10.1093/biomet/76.2.297.

    Article  Google Scholar 

  17. McCluskey SP, Plisson C, Rabiner EA, Howes O. Advances in CNS PET: the state-of-the-art for new imaging targets for pathophysiology and drug development. Eur J Nucl Med Mol Imaging. 2020;47:451–89. https://doi.org/10.1007/s00259-019-04488-0.

    Article  CAS  PubMed  Google Scholar 

  18. Cunningham VJ, Rabiner EA, Slifstein M, Laruelle M, Gunn RN. Measuring drug occupancy in the absence of a reference region: the Lassen plot re-visited. J Cereb Blood Flow Metab. 2010;30:46–50. https://doi.org/10.1038/jcbfm.2009.190.

    Article  PubMed  Google Scholar 

  19. Lingford-Hughes A, Hume SP, Feeney A, Hirani E, Osman S, Cunningham VJ, et al. Imaging the GABA-benzodiazepine receptor subtype containing the α5-subunit in vivo with [11C]Ro15 4513 positron emission tomography. J Cereb Blood Flow Metab. 2002;22:878–89. https://doi.org/10.1097/00004647-200207000-00013.

    Article  CAS  PubMed  Google Scholar 

  20. Martinez D, Hwang D-R, Mawlawi O, Slifstein M, Kent J, Simpson N, et al. Differential occupancy of somatodendritic and postsynaptic 5HT1A receptors by pindolol: a dose-occupancy study with [11C]WAY 100635 and positron emission tomography in humans. Neuropsychopharmacology. 2001;24:209–29. https://doi.org/10.1016/S0893-133X(00)00187-1.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by research grant AA021818.

Author information

Author notes

  1. Bart de Laat, Jocelyn Hoye and Heather Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA

    Bart de Laat, Jocelyn Hoye & Evan D. Morris

  2. Department of Psychiatry, Yale University, New Haven, CT, USA

    Evan D. Morris

  3. Department of Biomedical Engineering, Yale University, CT, New Haven, USA

    Heather Liu & Evan D. Morris

Authors
  1. Bart de Laat
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  2. Jocelyn Hoye
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  3. Heather Liu
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  4. Evan D. Morris
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Contributions

EDM and BDL developed this concept. HL wrote the original model-fitting code. JH wrote the simulation code. HL and JH and BDL analyzed the data. All the authors contributed to the manuscript.

Corresponding author

Correspondence to Evan D. Morris.

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This is a secondary analysis of data acquired under a protocol which was approved by the Yale ethical committee.

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Not applicable.

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The authors declare no competing interests.

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This article is part of the Topical Collection on Miscellanea

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de Laat, B., Hoye, J., Liu, H. et al. EC50 images, a novel endpoint from PET target occupancy studies, reveal spatial variation in apparent drug affinity. Eur J Nucl Med Mol Imaging 49, 1232–1241 (2022). https://doi.org/10.1007/s00259-021-05561-3

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  • DOI: https://doi.org/10.1007/s00259-021-05561-3

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