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European Journal of Nuclear Medicine and Molecular Imaging

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24-08-2022 | Positron Emission Tomography | Original Article

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [¹¹C]CHDI-00485180-R and [¹¹C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin

Authors: Aline Delva, Michel Koole, Kim Serdons, Guy Bormans, Longbin Liu, Jonathan Bard, Vinod Khetarpal, Celia Dominguez, Ignacio Munoz-Sanjuan, Andrew Wood, Mette Skinbjerg, Yuchuan Wang, Wim Vandenberghe, Koen Van Laere

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 1/2022

Abstract

Purpose

Huntington’s disease is caused by a trinucleotide expansion in the HTT gene, which leads to aggregation of mutant huntingtin (mHTT) protein in the brain and neurotoxicity. Direct in vivo measurement of mHTT aggregates in human brain parenchyma is not yet possible. In this first-in-human study, we investigated biodistribution and dosimetry in healthy volunteers of [¹¹C]CHDI-00485180-R ([¹¹C]CHDI-180R) and [¹¹C]CHDI-00485626 ([¹¹C]CHDI-626), two tracers designed for PET imaging of aggregated mHTT in the brain that have been validated in preclinical models.

Methods

Biodistribution and radiation dosimetry studies were performed in 3 healthy volunteers (age 25.7 ± 0.5 years; 2 F) for [¹¹C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [¹¹C]CHDI-626 using sequential whole-body PET-CT. Source organs were delineated in 3D using combined PET and CT data. Individual organ doses and effective doses were determined using OLINDA 2.1.

Results

There were no clinically relevant adverse events. The mean effective dose (ED) for [¹¹C]CHDI-180R was 4.58 ± 0.65 μSv/MBq, with highest absorbed doses for liver (16.9 μGy/MBq), heart wall (15.9 μGy/MBq) and small intestine (15.8 μGy/MBq). Mean ED for [¹¹C]CHDI-626 was 5.09 ± 0.06 μSv/MBq with the highest absorbed doses for the gallbladder (26.5 μGy/MBq), small intestine (20.4 μGy/MBq) and liver (19.6 μGy/MBq). Decay-corrected brain uptake curves showed promising kinetics for [¹¹C]CHDI-180R, but for [¹¹C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite.

Conclusion

[¹¹C]CHDI-180R and [¹¹C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most ¹¹C-ligands. While [¹¹C]CHDI-180R has promising kinetic properties in the brain, [¹¹C]CHDI-626 is not suitable for human in vivo mHTT PET due to the possibility of a radiometabolite accumulating in brain parenchyma.

Trial registration

EudraCT number 2020-002129-27. Clinicaltrials.gov NCT05224115 (retrospectively registered).

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Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, Leavitt BR, et al. Huntington disease Nat Rev Dis Primers. 2015;1:15005. https://doi.org/10.1038/nrdp.2015.5.CrossRefPubMed

Ferreira JJ, Rodrigues FB, Duarte GS, Mestre TA, Bachoud-Levi AC, Bentivoglio AR, et al. A MDS evidence-based review on treatments for Huntington’s disease. Mov Disord. 2021. https://doi.org/10.1002/mds.28855.CrossRefPubMedPubMedCentral

Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron. 2019;102:899. https://doi.org/10.1016/j.neuron.2019.05.001.CrossRefPubMed

Wild EJ, Boggio R, Langbehn D, Robertson N, Haider S, Miller JR, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J Clin Invest. 2015;125:1979–86. https://doi.org/10.1172/JCI80743.CrossRefPubMedPubMedCentral

Liu L, Prime ME, Lee MR, Khetarpal V, Brown CJ, Johnson PD, et al. Imaging mutant huntingtin aggregates: development of a potential PET ligand. J Med Chem. 2020;63:8608–33. https://doi.org/10.1021/acs.jmedchem.0c00955.CrossRefPubMed

Liu L, Johnson PD, Prime ME, Khetarpal V, Lee MR, Brown CJ, et al. [(11)C]CHDI-626, a PET tracer candidate for imaging mutant huntingtin aggregates with reduced binding to AD pathological proteins. J Med Chem. 2021;64:12003–21. https://doi.org/10.1021/acs.jmedchem.1c00667.CrossRefPubMed

Herrmann F, Hessmann M, Schaertl S, Berg-Rosseburg K, Brown CJ, Bursow G, et al. Pharmacological characterization of mutant huntingtin aggregate-directed PET imaging tracer candidates. Sci Rep. 2021;11:17977. https://doi.org/10.1038/s41598-021-97334-z.CrossRefPubMedPubMedCentral

Bertoglio D, Verhaeghe J, Miranda A, Wyffels L, Stroobants S, Mrzljak L, et al. Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease. Eur J Nucl Med Mol Imaging. 2021. https://doi.org/10.1007/s00259-021-05578-8.CrossRefPubMedPubMedCentral

Bertoglio D, Bard J, Hessmann M, Liu L, Gärtner A, De Lombaerde S, et al. Development of a ligand for in vivo imaging mutant huntingtin in Huntington’s disease. Sci Transl Med. 2022.

10.

Stabin MG, Siegel JA. RADAR dose estimate report: a compendium of radiopharmaceutical dose estimates based on OLINDA/EXM version 2.0. J Nucl Med. 2018;59:154–60. https://doi.org/10.2967/jnumed.117.196261.

11.

Zanotti-Fregonara P, Lammertsma AA, Innis RB. (11)C dosimetry scans should be abandoned. J Nucl Med. 2021;62:158–9. https://doi.org/10.2967/jnumed.120.257402.CrossRefPubMedPubMedCentral

12.

Zanotti-Fregonara P, Innis RB. Suggested pathway to assess radiation safety of 11C-labeled PET tracers for first-in-human studies. Eur J Nucl Med Mol Imaging. 2012;39:544–7. https://doi.org/10.1007/s00259-011-2005-8.CrossRefPubMed

13.

Radiation protection 99: Guidance on medical exposures in medical and biomedical research [cited 9/07/2021]. Available from: https://ec.europa.eu/energy/sites/ener/files/documents/099_en.pdf.; 1998.

14.

Leurquin-Sterk G, Celen S, Van Laere K, Koole M, Bormans G, Langlois X, et al. What we observe in vivo is not always what we see in vitro: development and validation of 11C-JNJ-42491293, a novel radioligand for mGluR2. J Nucl Med. 2017;58:110–6. https://doi.org/10.2967/jnumed.116.176628.CrossRefPubMed

Title: Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [11C]CHDI-00485180-R and [11C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin
Authors: Aline Delva
Michel Koole
Kim Serdons
Guy Bormans
Longbin Liu
Jonathan Bard
Vinod Khetarpal
Celia Dominguez
Ignacio Munoz-Sanjuan
Andrew Wood
Mette Skinbjerg
Yuchuan Wang
Wim Vandenberghe
Koen Van Laere
Publication date: 24-08-2022
Publisher: Springer Berlin Heidelberg
Keywords: Positron Emission Tomography
Huntington's Disease
Published in: European Journal of Nuclear Medicine and Molecular Imaging / Issue 1/2022
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05945-z

At a glance: The STEP trials

Springer Medicine

Biodistribution and dosimetry in human healthy volunteers of the PET radioligands [¹¹C]CHDI-00485180-R and [¹¹C]CHDI-00485626, designed for quantification of cerebral aggregated mutant huntingtin

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

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