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

Abstract

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo [4,5]imidazo[1,2a]pyrimidine series that show selective binding to mHTT aggregates over Aβ-and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [ 11 C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.

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

“…We report here the kinetic properties and longitudinal quantification of the novel radioligand [ 11 C]CHDI-626 for PET imaging of mHTT in the living brain. Based on our recent report [16], we first assessed the stability and kinetic properties of the radioligand to determine the optimal protocol for the longitudinal study. Plasma analysis revealed a rapid disappearance of [ 11 C]CHDI-626 with the detection of at least 2 species of metabolites that were polar and appeared not to penetrate the blood-brain barrier as previously suggested [16].…”

“…Based on our recent report [ 16 ], we first assessed the stability and kinetic properties of the radioligand to determine the optimal protocol for the longitudinal study. Plasma analysis revealed a rapid disappearance of [ 11 C]CHDI-626 with the detection of at least 2 species of metabolites that were polar and appeared not to penetrate the blood–brain barrier as previously suggested [ 16 ]. The radioligand almost completely disappeared by 25 min, apparently due to metabolism, and its contribution to the input function was nearly absent at 15 min following injection.…”

“…The collected fraction was sterile-filtered and diluted with saline to decrease the EtOH concentration below 10%. The radiochemical purity of the produced [ 11 C]CHDI-626 was greater than 99%, determined as recently described [ 16 ], with a molar activity of 189.7 ± 58.6 GBq/µmol. The tritiated version of the radioligand, namely [ 3 H]CHDI-626, was synthesized by Pharmaron, UK, with radiochemical purity of 98.7% and molar activity of 3.07 GBq/µmol.…”

“…A notable property of the mHTT PET radioligands currently under investigation is affinity towards amyloid plaques in post-mortem human tissue that might reduce their specificity [ 15 ], and efforts to overcome this issue are currently focused on the development of radioligands with high affinity and selectivity towards mHTT aggregates suitable for clinical applications. We have recently reported the development of a novel high-affinity radioligand, CHDI-626, that targets mHTT and lacks significant affinity towards amyloid plaques, representing a potential candidate for mHTT PET imaging in the clinic [ 16 , 17 ].…”

Synthesis and Evaluation of a Fluorine-18 Radioligand for Imaging Huntingtin Aggregates by Positron Emission Tomographic Imaging

“…Thus a PET imaging agent for m HTT could be expected to have similar benefits to the amyloid, tau and α-synuclein PET imaging agents currently used for dementia imaging ( Mathis et al, 2017 ), allowing diagnosis of HD, monitoring of disease progression, and evaluating patient response to HD modifying therapies targeting m HTT. The only example to date for imaging m HTT is with the 11 C-labeled agents [ 11 C]CHDI-180R and [ 11 C]CHDI-626 which exhibit high affinity (low nanomolar IC 50 ) toward m HTT and have selectivity over other protein aggregates like amyloid and tau ( Dominguez et al, 2016 ; Liu et al, 2020 , 2021 ; Bertoglio et al, 2021 ). To the best of our knowledge, there are currently no 18 F-labeled PET imaging agents for imaging huntingtin protein aggregates described in the literature.…”