The study investigators have developed two novel PET radioligands that will be evaluated for their suitability for use in clinical research settings to quantify mHTT in HDGECs. The PET radioligands do not have any pharmacological effect at the microdoses (total dose \<100ug) at which they will be administered; they will not be administered at pharmacological doses. This study has a modular design in two phases, and each phase will enroll a small independent cohort. The execution of each subsequent phase is dependent on results from the previous phase.

Phase 1 is the initial evaluation of the PET radioligands. A suitable PET radioligand is expected to produce quantifiably higher binding in HD participants' brains compared to young HC participants' brains (since they do not express mHTT). Phase 1 is divided in two sub phases: Phase 1a will evaluate the basic safety and kinetic properties as well as brain uptake in three (3) young HCs; Phase 1b will test the difference in binding in six (6) HDGECs with Stage II HD compared to six (6) young HCs (three (3) young HCs will be imaged in addition to the three (3) young HCs from 1a. The rationale behind using young HCs in Phase 1 is to screen out HC participants who may have undiagnosed amyloid-β (Aβ) plaques, a potential off-target binding site for \[¹¹C\]CHDI-00485180-R. The rationale behind imaging HDGECs with Stage II HD in Phase 1 is based on the hypothesis that the density of mHTT aggregates increases with disease severity, and the ability to detect a difference in binding between HCs and HDGECs is expected to be higher in Stage II HD (more severe stages of HD will not be included in this study). An option to image three (3) pre-manifest HDGECs from Phase 2c (see below) will be included in case the results indicate that brain atrophy (i.e., loss of aggregate due to atrophy) affects the binding and evaluation of the PET radioligands in HDGECs with Stage II HD. For each of the two PET radioligands a Go/ No-Go evaluation will take place (for overview see Figure 1); if satisfactory results are not obtained for a particular radioligand, then that radioligand will not progress to evaluation in further phases. Promising results for either radioligand will lead to that particular radioligand continuing to Phase 2 evaluation.

Phase 2 will evaluate the sensitivity of the PET radioligand(s) to discriminate between different stages and severity of HD. In addition, a TRT in Phase 2 will evaluate the variability of repeated imaging for the PET radioligand. Phase 2 has a sequential design in sub phases that will assess the sensitivity of the radioligand in descending severity of HD: 2a in six (6) HDGECs with Stage II HD and six (6) age-matched controls; 2b in six (6) HDGECs with Stage I HD and six (6) age-matched controls; 2c in six (6) premanifest HDGECs and six (6) age-matched controls. The rationale for imaging groups of descending HD severity is based on the hypothesis that the density of mHTT aggregates increases with disease severity, and the ability to detect a difference in binding between HCs and HDGECs is expected to be lowest in the premanifest stage. This design will enable a stepwise assessment of the sensitivity of the PET radioligands. After each sub-phase a Go/No-Go evaluation will take place; if satisfactory results are not obtained for a particular radioligand then that radioligand will not be evaluated in further sub-phases. Promising results for either radioligand will lead to that particular radioligand continuing to the next sub-phase.

This study design allows each radioligand to be reviewed and analyzed after evaluation in each cohort. The progression through each level of analysis will indicate whether either or both radioligands will measure mHTT aggregate levels with sufficient sensitivity to become potential disease progression and efficacy biomarker(s) in HDGECs.