Imaging Autotaxin <i>In Vivo</i> with <sup>18</sup>F-Labeled Positron Emission Tomography Ligands.
Deng X, Salgado-Polo F, Shao T, Xiao Z, Van R, Chen J, Rong J, Haider A, Shao Y, Josephson L, Perrakis A, Liang SH.
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-<i>a</i>]pyridine derivatives, determined their inhibition constants, and confirmed their binding mode by crystallographic analysis. Based on their promising <i>in vitro</i> properties, compounds <b>9c</b>, <b>9f</b>, <b>9h</b>, and <b>9j</b> were radiofluorinated. Also, a deuterated analog of [<sup>18</sup>F]<b>9j</b>, designated as [<sup>18</sup>F]ATX-1905 ([<sup>18</sup>F]<b>20</b>), was designed and proved to be highly stable against <i>in vivo</i> radiodefluorination compared with [<sup>18</sup>F]<b>9c</b>, [<sup>18</sup>F]<b>9f</b>, [<sup>18</sup>F]<b>9h</b>, and [<sup>18</sup>F]<b>9j</b>. These results along with <i>in vitro</i> and <i>in vivo</i> studies toward ATX in a mouse model of LPS-induced liver injury suggest that [<sup>18</sup>F]ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.