Synthesis, radiolabeling, and evaluation of a potent β-site APP cleaving enzyme (BACE1) inhibitor for PET imaging of BACE1 in vivo

Lili Pan; Qian He; Yi Wu; Ni Zhang; Huawei Cai; Bo Yang; Yuxi Wang; Yunchun Li; Xiaoai Wu

doi:10.1016/j.bmcl.2022.128543

Synthesis, radiolabeling, and evaluation of a potent β-site APP cleaving enzyme (BACE1) inhibitor for PET imaging of BACE1 in vivo

Bioorg Med Chem Lett. 2022 Mar 1:59:128543. doi: 10.1016/j.bmcl.2022.128543. Epub 2022 Jan 12.

Authors

Lili Pan¹, Qian He², Yi Wu³, Ni Zhang⁴, Huawei Cai¹, Bo Yang⁵, Yuxi Wang⁶, Yunchun Li⁷, Xiaoai Wu⁸

Affiliations

¹ Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China.
² Department of Emergency, West China Hospital, Sichuan University, Chengdu 610000, Sichuan, China.
³ Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Gannan Medical University, Ganzhou 341000, China.
⁴ Department of Psychiatry, West China Hospital of Sichuan University, Chengdu 610041, China.
⁵ Department of Pharmacy, Panzhihua Central Hospital, Panzhihua, Sichuan, 617067, China.
⁶ Department of Respiratory and Critical Care Medicine, West China Medical School/West China Hospital, Sichuan University, Chengdu 610000, China.
⁷ Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Nuclear Medicine, The Second People's Hospital of Yibin, Yibin 644000, Sichuan, China. Electronic address: ycliwc@163.com.
⁸ Department of Nuclear Medicine, Laboratory of Clinical Nuclear Medicine, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: xiaoai.wu@hotmail.com.

PMID: 35031452
DOI: 10.1016/j.bmcl.2022.128543

Abstract

The β-site APP-cleaving enzyme 1 (BACE1) plays important roles in the proteolytic processing of amyloid precursor protein, and can be regarded as an important target for the diagnosis and treatment of AD. This study aimed to report the synthesis and evaluation of an ¹⁸F-labeled 2-amino-3,4-dihydroquinazoline analog as a potential BACE1 radioligand. A fluoropropyl side chain was introduced to the phenyl of this 3,4-dihydroquinazoline scaffold to generate the radioligand. Our preliminary data indicated that although the 2-amino-3,4-dihydroquinazoline scaffold possessed favorable in-vitro properties as a PET ligand, its poor brain uptake hindered the in-vivo imaging of BACE1. Further investigation would be required to optimize the scaffold for the development of a blood-brain-barrier-permeable BACE1-targeted PET ligand.

Keywords: Blood-brain-barrier; Fluoropropyl side chain; Radioligand; β-Site APP-cleaving enzyme 1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / analysis
Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / analysis
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Fluorine Radioisotopes
Humans
Isotope Labeling
Ligands
Molecular Structure
Positron-Emission Tomography*
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Fluorine Radioisotopes
Ligands
Quinazolinones
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human
Fluorine-18