Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain.
Lei ZhangLaigao ChenJason K DutraElizabeth M BeckSangram NagAkihiro TakanoNahid AminiRyosuke ArakawaMichael A BrodneyLeanne M BuzonShawn D DoranLorraine F LanyonTimothy J McCarthyKelly R BalesCharles E NolanBrian T O'NeillKlaas SchildknegtChrister HalldinAnabella VillalobosPublished in: Journal of medicinal chemistry (2018)
Alzheimer's disease (AD) is characterized by accumulation of β-amyloid (Aβ) plaques and neurofibrillary tau tangles in the brain. β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a key role in the generation of Aβ fragments via extracellular cleavage of the amyloid precursor protein (APP). We became interested in developing a BACE1 PET ligand to facilitate clinical assessment of BACE1 inhibitors and explore its potential in the profiling and selection of patients for AD trials. Using a set of PET ligand design parameters, compound 3 (PF-06684511) was rapidly identified as a lead with favorable in vitro attributes and structural handles for PET radiolabeling. Further evaluation in an LC-MS/MS "cold tracer" study in rodents revealed high specific binding to BACE1 in brain. Upon radiolabeling, [18F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans.
Keyphrases
- positron emission tomography
- computed tomography
- pet ct
- pet imaging
- resting state
- white matter
- functional connectivity
- high resolution
- end stage renal disease
- cerebral ischemia
- protein protein
- ejection fraction
- prognostic factors
- chronic kidney disease
- binding protein
- cerebrospinal fluid
- peritoneal dialysis
- transcription factor
- patient reported
- blood brain barrier