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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Acknowledgements
This work was supported by CHDI Foundation, Inc. Aline Delva is a PhD fellow of the Fund for Scientific Research Flanders (FWO). Koen van Laere and Wim Vandenberghe are Senior Clinical Investigators of the FWO. The authors are grateful to the study participants, and to Kwinten Porters and Jef Van Loock for their contribution to the scanning and data handling.
Funding
This work was supported by CHDI Foundation Inc., a nonprofit biomedical research organization exclusively dedicated to collaboratively developing therapeutics that substantially improve the lives of those affected by Huntington’s disease. AD is a PhD fellow of the Fund for Scientific Research Flanders (FWO). KVL and WV are Senior Clinical Investigators of the FWO.
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Conception and design of the study were done by MK, KS, GB, LL, JB, VK, CD, IM-S, AW, MS, YW, WV and KVL. Radiotracer development was led by LL, JB, VK, CD, IM, AW and MS, while GMP optimization was done by KS and GB. The acquisition and analysis of the data were performed by AD, MK, KS, WV and KVL. The manuscript draft was done by AD, MK, MS, WV and KVL. The manuscript has been revised and approved by all authors.
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All procedures were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study has been approved by the institutional review board (University hospitals and KU Leuven Ethics Committee) and performed in accordance with the World Medical Association Declaration of Helsinki. Written informed consent was obtained from all the participants before study inclusion.
Competing interests
AD is a PhD fellow of the Fund for Scientific Research Flanders (FWO). KVL and WV are Senior Clinical Investigators of the FWO. MK has no financial interests. JB, LL, AW, VK, YW, MS, CD, and IM-S are employed by CHDI Management, Inc. as advisors to CHDI Foundation, Inc. The radioligands have been provided by CHDI, USA, and the human imaging study has been performed in Leuven, Belgium, under contract between CHDI and KU Leuven. The following granted patent is related to this work: Probes for Imaging Huntingtin Proteins, International Publication Number WO 2016/033445 Al (published on 3 March 2016 with filing number #PCT/US2015/047407) for [11C]CHDI-180R, and WO 2017/040336 A1 (published on 9 March 2017 with filing number #PCT/US2016/049112) for [11C]CHDI-626.
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Delva, A., Koole, M., Serdons, K. et al. 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. Eur J Nucl Med Mol Imaging 50, 48–60 (2022). https://doi.org/10.1007/s00259-022-05945-z
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DOI: https://doi.org/10.1007/s00259-022-05945-z