18F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging

Xiaodan An; Jingqi Wang; Linjiang Tong; Xiaojun Zhang; Hualong Fu; Jinming Zhang; Hua Xie; Yiyun Huang; Hongmei Jia

doi:10.1016/j.bmc.2023.117233

¹⁸F-Labeled o‑aminopyridyl alkynyl radioligands targeting colony-stimulating factor 1 receptor for neuroinflammation imaging

Bioorg Med Chem. 2023 Apr 1:83:117233. doi: 10.1016/j.bmc.2023.117233. Epub 2023 Mar 8.

Authors

Xiaodan An¹, Jingqi Wang¹, Linjiang Tong², Xiaojun Zhang³, Hualong Fu¹, Jinming Zhang⁴, Hua Xie⁵, Yiyun Huang⁶, Hongmei Jia⁷

Affiliations

¹ Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China.
² Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
³ Nuclear Medicine Department, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China.
⁴ Nuclear Medicine Department, the First Medical Center of Chinese PLA General Hospital, Beijing 100853, China. Electronic address: zhangjm301@163.com.
⁵ Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China. Electronic address: hxie@simm.ac.cn.
⁶ Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT 06520-8048, USA. Electronic address: henry.huang@yale.edu.
⁷ Key Laboratory of Radiopharmaceuticals (Beijing Normal University), Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China. Electronic address: hmjia@bnu.edu.cn.

PMID: 36933438
DOI: 10.1016/j.bmc.2023.117233

Abstract

We report the design, synthesis and evaluation of five o‑aminopyridyl alkynyl derivatives as colony-stimulating factor 1 receptor (CSF-1R) ligands. Compounds 4 and 5 with the fluoroethoxy group at the meta- or para-position of the phenyl ring possessed nanomolar inhibitory potency against CSF-1R with IC₅₀ values of 7.6 nM and 2.3 nM, respectively. Radioligands [¹⁸F]4 and [¹⁸F]5 were obtained in radiochemical yields of 17.2 ± 5.3% (n = 5, decay-corrected) and 14.0 ± 4.3% (n = 4, decay-corrected), with radiochemical purity of > 99% and molar activity of 9-12 GBq/μmol (n = 5) and 6-8 GBq/μmol (n = 4), respectively. In biodistribution studies, radioligands [¹⁸F]4 and [¹⁸F]5 showed moderate brain uptake in male ICR mice with 1.52 ± 0.15 and 0.91 ± 0.07% ID/g, respectively, at 15 min. Metabolic stability studies in mouse brain revealed that [¹⁸F]4 exhibited high stability while [¹⁸F]5 suffered from low stability. Higher accumulation of [¹⁸F]4 in the brain of lipopolysaccharide (LPS)-treated mice was observed, and further pretreatment of BLZ945 or CPPC led to remarkable reduction, indicating specific binding of [¹⁸F]4 to CSF-1R.

Keywords: (18)F; Alzheimer’s disease; Colony-stimulating factor 1 receptor; Microglia; Neuroinflammation.

Publication types

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

MeSH terms

Aminopyridines* / chemistry
Aminopyridines* / pharmacology
Animals
Fluorine Radioisotopes* / chemistry
Male
Mice
Mice, Inbred ICR
Neuroinflammatory Diseases* / diagnostic imaging
Positron-Emission Tomography* / methods
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor* / chemistry
Tissue Distribution

Substances

Fluorine Radioisotopes
Aminopyridines
Csf1r protein, mouse
Receptors, Granulocyte-Macrophage Colony-Stimulating Factor