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

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 [ 11 C]CHDI-00485180-R ([ 11 C]CHDI-180R) and [ 11 C]CHDI-00485626 ([ 11 C]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 [ 11 C]CHDI-180R and in 3 healthy volunteers (age 35.3 ± 6.8 years; 2 F) for [ 11 C]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 [ 11 C]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 [ 11 C]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 [ 11 C]CHDI-180R, but for [ 11 C]CHDI-626 an increasing signal over time was found, probably due to accumulation of a brain-penetrant metabolite. Conclusion [ 11 C]CHDI-180R and [ 11 C]CHDI-626 are safe for in vivo PET imaging in humans. The estimated radiation burden is in line with most 11 C-ligands. While [ 11 C]CHDI-180R has promising kinetic properties in the brain, [ 11 C]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).