Longitudinal Preclinical Evaluation of the Novel Radioligand [11C]CHDI-626 for PET Imaging of Mutant Huntingtin Aggregates in Huntington’s Disease

Abstract

PurposeAs 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.MethodsAfter 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.ResultsDespite fast metabolism and kinetics, the radioligand was suitable for PET imaging of mHTT. Longitudinal quantification could discriminate between genotypes already at premanifest stage (3M), 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.ConclusionWith 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.

Development of a ligand for in vivo imaging of mutant huntingtin in Huntington’s disease

“…To evaluate regional pharmacological effects of candidate therapeutics targeting mHTT, we sought to develop a noninvasive imaging agent specific for aggregated mHTT that could give insight into the timing, durability, and regional therapeutic effects of administered drugs ( 8 – 10 ). As all current therapeutic agents in development ( 11 ) target either HTT or HTT transcriptional or posttranscriptional processes, quantification of mHTT protein could offer a good indicator of the extent of HTT lowering and of the biodistribution of the agents.…”

“…Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works the timing, durability, and regional therapeutic effects of administered drugs (8)(9)(10). As all current therapeutic agents in development (11) target either HTT or HTT transcriptional or posttranscriptional processes, quantification of mHTT protein could offer a good indicator of the extent of HTT lowering and of the biodistribution of the agents.…”

“…As all current therapeutic agents in development (11) target either HTT or HTT transcriptional or posttranscriptional processes, quantification of mHTT protein could offer a good indicator of the extent of HTT lowering and of the biodistribution of the agents. [ 11 C]CHDI-180R was identified and developed into a positron emission tomography (PET) tracer through a medicinal chemistry campaign from an initial small-molecule screen that yielded mHTT aggregate binders (8)(9)(10). CHDI-180 is a high-affinity (1 to 3 nM), cell-permeable ligand, specific for mHTT aggregates and unable to bind unexpanded HTT, monomeric soluble mHTT, or nuclear inclusion bodies.…”

[11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins

“…As noted in the table, the unusually negative percentage displacement (−29%) observed for 14 in the AD_bh RBA assay may be an indication that this compound binds strongly to the AD brain homogenate. Although higher f u,b values were achieved with pyridazinone (17,18), pyridone (19, 20), and pyrimidone (22) amides, these analogues were also of lower potency. A precipitous drop of affinity was seen when the amide NH in pyridone 20 was methylated (21), which likely disfavors the planar conformation of the pyridine ring (N-aryl dihedral change: 25 → 62°, estimated from minimization of the amide bond using MOE 18 ).…”

“…These data suggest that compound 2 is a highly specific binder to mHTT exon-1 and specifically to aggregates. The ability of 2 to quantitatively detect mHTT exon-1 aggregate levels during the course of disease progression was demonstrated in a longitudinal PET imaging study 22 with HET zQ175 knock-in mice. 23,24 More importantly, the observed binding specificity of 2 in the HD mouse model is translatable to the mHTT aggregate in postmortem HD brains, further supporting the clinical development of this ligand.…”