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European Journal of Nuclear Medicine and Molecular Imaging

Erschienen in:

24.08.2022 | 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

verfasst von: 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

Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging | Ausgabe 1/2022

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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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Titel: 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
verfasst von: 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
Publikationsdatum: 24.08.2022
Verlag: Springer Berlin Heidelberg
Erschienen in: European Journal of Nuclear Medicine and Molecular Imaging / Ausgabe 1/2022
Print ISSN: 1619-7070
Elektronische ISSN: 1619-7089
DOI: https://doi.org/10.1007/s00259-022-05945-z

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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

Live-Webinar "Chronische Unterbauch- und Viszeralschmerzen in der Praxis managen"

Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

Trial registration

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