Imaging Mutant Huntingtin Aggregates: Development of a Potential PET Ligand.
Longbin LiuMichael E PrimeMatt R LeeVinod KhetarpalChristopher J BrownPeter D JohnsonPatricia Miranda-AzpiazuXuemei ChenDaniel Clark-FrewSamuel CoeRandall DavisAnthony DickieAndreas EbnethSimone EspositoElise GadouleauXinjie GaiSebastien GalanSamantha GreenCatherine GreenawayPaul GilesChrister HalldinSarah HayesTodd HerbstFrank HerrmannManuela HeßmannZhisheng JiaAlexander KiselyovAdrian KoteyThomas KrulleJohn E MangetteRichard W MarstonSergio MentaMatthew R MillsEdith MonteagudoSangram NagMartina NibbioLaura OrsattiSabine SchaertlChristoph ScheichJoanne SprostonVladimir StepanovMarie SvedbergAkihiro TakanoMalcolm TaylorWayne ThomasMiklós TothDarshan VaidyaKatarina VanräsDerek WeddellIan WiggintonJohn WityakLadislav MrzljakIgnacio Munoz-SanjuanJonathan A BardCelia DominguezPublished in: Journal of medicinal chemistry (2020)
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.
Keyphrases
- pet imaging
- positron emission tomography
- computed tomography
- endothelial cells
- high resolution
- pet ct
- binding protein
- case control
- resting state
- mouse model
- induced pluripotent stem cells
- white matter
- small molecule
- pluripotent stem cells
- wild type
- social media
- adipose tissue
- amino acid
- functional connectivity
- high throughput
- risk assessment
- dna binding
- high fat diet induced
- blood brain barrier
- cerebral ischemia
- fluorescence imaging
- climate change
- photodynamic therapy
- insulin resistance