Imaging Autotaxin In Vivo with 18 F-Labeled Positron Emission Tomography Ligands

• Published in: Journal of medicinal chemistry Vol. 64; no. 20; pp. 15053 - 15068
• Main Authors: Deng, Xiaoyun, Salgado-Polo, Fernando, Shao, Tuo, Xiao, Zhiwei, Van, Richard, Chen, Jiahui, Rong, Jian, Haider, Ahmed, Shao, Yihan, Josephson, Lee, Perrakis, Anastassis, Liang, Steven H
• Format: Journal Article
• Language: English
• Published: United States 28.10.2021
• Subjects: Animals; Dose-Response Relationship, Drug; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Fluorine Radioisotopes; Ligands; Mice; Molecular Structure; Phosphoric Diester Hydrolases - analysis; Phosphoric Diester Hydrolases - metabolism; Positron-Emission Tomography; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.1c00913

Autotaxin (ATX) is a secreted phosphodiesterase that has been implicated in a remarkably wide array of pathologies, especially in fibrosis and cancer. While ATX inhibitors have entered the clinical arena, a validated probe for positron emission tomography (PET) is currently lacking. With the aim to develop a suitable ATX-targeted PET radioligand, we have synthesized a focused library of fluorinated imidazo[1,2- ]pyridine derivatives, determined their inhibition constants, and confirmed their binding mode by crystallographic analysis. Based on their promising properties, compounds , , , and were radiofluorinated. Also, a deuterated analog of [ F] , designated as [ F]ATX-1905 ([ F] ), was designed and proved to be highly stable against radiodefluorination compared with [ F] , [ F] , [ F] , and [ F] . These results along with and studies toward ATX in a mouse model of LPS-induced liver injury suggest that [ F]ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.