Identification of a Novel Positron Emission Tomography (PET) Ligand for Imaging β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE-1) in Brain.

Autor:	Zhang L; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Chen L; Clinical & Translational Imaging, Early Clinical Development , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Dutra JK; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Groton , Connecticut 06340 , United States., Beck EM; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Nag S; Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden., Takano A; Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden., Amini N; Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden., Arakawa R; Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden., Brodney MA; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Buzon LM; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Groton , Connecticut 06340 , United States., Doran SD; Medicine Design, Pharmacokinetics, Dynamics and Metabolism , Pfizer Inc. , Groton , Connecticut 06340 , United States., Lanyon LF; Medicine Design, Pharmacokinetics, Dynamics and Metabolism , Pfizer Inc. , Groton , Connecticut 06340 , United States., McCarthy TJ; Clinical & Translational Imaging, Early Clinical Development , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Bales KR; Internal Medicine , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., Nolan CE; Internal Medicine , Pfizer Inc. , Cambridge , Massachusetts 02139 , United States., O'Neill BT; Medicine Design, Medicinal Chemistry , Pfizer Inc. , Groton , Connecticut 06340 , United States., Schildknegt K; Pharmaceutical Sciences , Pfizer Inc. , Groton , Connecticut 06340 , United States., Halldin C; Department of Clinical Neuroscience, Center for Psychiatry Research , Karolinska Institutet and Stockholm County Council , SE-17176 Stockholm , Sweden., Villalobos A; Medicinal Synthesis Technologies , Pfizer Inc. , Groton , Connecticut 06340 , United States.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2018 Apr 26; Vol. 61 (8), pp. 3296-3308. Date of Electronic Publication: 2018 Feb 02.
DOI:	10.1021/acs.jmedchem.7b01769
Abstrakt:	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, [ 18 F]3 demonstrated favorable brain uptake and high in vivo specificity in nonhuman primate (NHP), suggesting its potential for imaging BACE1 in humans.
Databáze:	MEDLINE
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