Longitudinal preclinical evaluation of the novel radioligand [11C]CHDI-626 for PET imaging of mutant huntingtin aggregates in Huntington’s disease

Abstract

Purpose As several therapies aimed at lowering mutant huntingtin (mHTT) brain levels in Huntington’s disease (HD) are currently being investigated, noninvasive positron emission tomography (PET) imaging of mHTT could be utilized to directly evaluate therapeutic efficacy and monitor disease progression. Here we characterized and longitudinally assessed the novel radioligand [11C]CHDI-626 for mHTT PET imaging in the zQ175DN mouse model of HD. Methods After evaluating radiometabolites and radioligand kinetics, we conducted longitudinal dynamic PET imaging at 3, 6, 9, and 13 months of age (M) in wild-type (WT, n = 17) and heterozygous (HET, n = 23) zQ175DN mice. Statistical analysis was performed to evaluate temporal and genotypic differences. Cross-sectional cohorts at each longitudinal time point were included for post-mortem [3H]CHDI-626 autoradiography. Results Despite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3 M), showing an age-associated increase in signal in HET mice in parallel with mHTT aggregate load progression, as supported by the post-mortem [3H]CHDI-626 autoradiography. Conclusion With clinical evaluation underway, [11C]CHDI-626 PET imaging appears to be a suitable preclinical candidate marker to monitor natural HD progression and for the evaluation of mHTT-lowering therapies.

PET Ligands for Imaging Mutant Huntingtin Aggregates: A Case Study in Non‐For‐Profit Scientific Management

“…Longitudinal preclinical evaluation of [ 11 C]CHDI-626 in the zQ175DN mouse model is described by Bertoglio and co-workers. [48] In 2022, the results from a first-in-human study of [ 11 C]CHDI-180R and [ 11 C]CHDI-626 in three healthy volunteers were published. [49] Both radiotracers were deemed safe for in vivo PET imaging in humans, with brain uptakes of up to 3.5 %ID/g.…”

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates

“…To introduce modifications to the LHS methoxy moiety of 1 with either a fluoroethyl (8) or trifluoroethyl (9) group, the general approach shown in Scheme 3 was followed. Phenol 29 was prepared as previously described.…”

“…HRMS (ES + ) m/z: 335.1139 (335.1143 calcd for C 18 H 14 N 4 O 3 M + H). (8). This material was synthesized according to General Procedure E as described above using intermediate 40 (see Supporting Information for synthesis).…”

“…However, keeping the RHS pyridazinone and varying the other end of 1 were met with increased AD binding. For example, simple modifications of the left-hand side (LHS) methoxy moiety of 1 with either a fluoroethyl (8) or a trifluoroethyl (9) group led to increased AD binding (91% and 77%, respectively) although good potency was retained in the Exon1-Q46_RBA assay (0.4−0.6 nM). The trifluoromethyl compound 9 was recently reported as a possible 18 F-PET mHTT ligand.…”

“…We have shown that aggregates derived either from polyglutamine (Q46) itself or from recombinant mHTT exon1 are suitable surrogates to identify binders of mHTT aggregates using radioligand binding assays (RBAs) . That work culminated in the identification of first-generation mHTT PET ligands, , their subsequent validation in mHTT-lowering therapy imaging studies in preclinical models, , and ultimately advancement to clinical evaluation . These first-generation PET ligands were based on the 11 C-radioisotope with a short decaying half-life ( t 1/2 = 20.4 min) that limits both the accessibility and imaging window of these ligands.…”