Mutant
huntingtin (mHTT) protein carrying the elongated N-terminal
polyglutamine (polyQ) tract misfolds and forms protein aggregates
characteristic of Huntington’s disease (HD) pathology. A high-affinity
ligand specific for mHTT aggregates could serve as a positron emission
tomography (PET) imaging biomarker for HD therapeutic development
and disease progression. To identify such compounds with binding affinity
for polyQ aggregates, we embarked on systematic structural activity
studies; lead optimization of aggregate-binding affinity, unbound
fractions in brain, permeability, and low efflux culminated in the
discovery of compound 1, which exhibited target engagement
in autoradiography (ARG) studies in brain slices from HD mouse models
and postmortem human HD samples. PET imaging studies with 11C-labeled 1 in both HD mice and WT nonhuman primates
(NHPs) demonstrated that the right-hand-side labeled ligand [11C]-1R (CHDI-180R) is a suitable PET tracer for
imaging of mHTT aggregates. [11C]-1R is now
being advanced to human trials as a first-in-class HD PET radiotracer.
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.
Huntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (
HTT
) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) tract. Whereas several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, methods to visualize mHTT protein species in the living brain are lacking. Here, we demonstrate the development and characterization of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with
11
C ([
11
C]CHDI-180R) allowed noninvasive monitoring of mHTT pathology in the brain and could track region- and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression in a rodent model. We further showed that in these animals, therapeutic agents that lowered mHTT in the striatum had a functional restorative effect that could be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.
Therapeutic interventions are being developed for Huntington’s
disease (HD), a hallmark of which is mutant huntingtin protein (mHTT)
aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further
optimization were identified. We replaced the pyridazinone ring of
CHDI-180 with a pyrimidine ring and minimized off-target binding using
brain homogenate derived from Alzheimer’s disease patients.
The major in vivo metabolic pathway via aldehyde
oxidase was blocked with a 2-methyl group on the pyrimidine ring.
A strategically placed ring-nitrogen on the benzoxazole core ensured
high free fraction in the brain without introducing efflux. Replacing
a methoxy pendant with a fluoro-ethoxy group and introducing deuterium
atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows
a rapid brain uptake and washout profile in non-human primates and
is now being advanced to human testing.
The development of facile, wide scope synthetic methodologies providing access to fluorinated motifs is important in medic-inal chemistry; for our purposes, we are interested in developing fluorine-tagged compounds to investigate their utility in Huntington’s disease. Here, we describe a novel, operationally simple and mild procedure for the synthesis of mono-fluoromethyl 6,5-heteroaromatic bicycles using 1,3-difluoroacetone (DFA). The scope of the reaction was investigated, and 27 examples synthesized with yields up to 96%.
The development of facile, wide scope synthetic methodologies providing access to fluorinated motifs is important in medic-inal chemistry; for our purposes, we are interested in developing fluorine-tagged compounds to investigate their utility in Huntington’s disease. Here, we describe a novel, operationally simple and mild procedure for the synthesis of mono-fluoromethyl 6,5-heteroaromatic bicycles using 1,3-difluoroacetone (DFA). The scope of the reaction was investigated, and 27 examples synthesized with yields up to 96%.
The development of facile, wide scope synthetic methodologies providing access to fluorinated motifs is important in medic-inal chemistry; for our purposes, we are interested in developing fluorine-tagged compounds to investigate their utility in Huntington’s disease. Here, we describe a novel, operationally simple and mild procedure for the synthesis of mono-fluoromethyl 6,5-heteroaromatic bicycles using 1,3-difluoroacetone (DFA). The scope of the reaction was investigated, and 27 examples synthesized with yields up to 96%.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.