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

被引：6

作者：

Deng, Xiaoyun ^{[1
,2
,3
]}

Salgado-Polo, Fernando ^{[4
,5
]}

Shao, Tuo ^{[1
,2
]}

Xiao, Zhiwei ^{[1
,2
]}

Van, Richard ^{[6
]}

Chen, Jiahui ^{[1
,2
]}

Rong, Jian ^{[1
,2
]}

Haider, Ahmed ^{[1
,2
]}

Shao, Yihan ^{[6
]}

Josephson, Lee ^{[1
,2
]}

Perrakis, Anastassis ^{[4
,5
]}

Liang, Steven H. ^{[1
,2
]}

机构：

[1] Harvard Med Sch, Massachusetts Gen Hosp, Div Nucl Med & Mol Imaging, Boston, MA 02114 USA

[2] Harvard Med Sch, Dept Radiol, Boston, MA 02114 USA

[3] Huazhong Univ Sci & Technol, Tongji Hosp, Tongji Med Coll, Dept Nucl Med, Wuhan 430030, Peoples R China

[4] Netherlands Canc Inst, Oncode Inst, NL-1066 CX Amsterdam, Netherlands

[5] Netherlands Canc Inst, Div Biochem, NL-1066 CX Amsterdam, Netherlands

[6] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2021年 / 64卷 / 20期

基金：

瑞士国家科学基金会;

关键词：

LYSOPHOSPHATIDIC ACID; STRUCTURAL BASIS; EXPRESSION; DISCOVERY; INHIBITORS; PROMOTES; IDENTIFICATION; ACTIVATION; EVOLUTION; FIBROSIS;

D O I：

10.1021/acs.jmedchem.1c00913

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-a]pyridine derivatives, determined their inhibition constants, and confirmed their binding mode by crystallographic analysis. Based on their promising in vitro properties, compounds 9c, 9f, 9h, and 9j were radiofluorinated. Also, a deuterated analog of [F-18]9j, designated as [F-18]ATX-1905 ([F-18]20), was designed and proved to be highly stable against in vivo radiodefluorination compared with [F-18]9c, [F-18]9f, [F-18]9h, and [F-18]9j. These results along with in vitro and in vivo studies toward ATX in a mouse model of LPS-induced liver injury suggest that [F-18]ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.

引用

页码：15053 / 15068

页数：16

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