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

Abstract

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 [18F]9j, designated as [18F]­ATX-1905 ([18F]20), was designed and proved to be highly stable against in vivo radiodefluorination compared with [18F]9c, [18F]9f, [18F]9h, and [18F]9j. These results along with in vitro and in vivo studies toward ATX in a mouse model of LPS-induced liver injury suggest that [18F]­ATX-1905 is a suitable PET probe for the non-invasive quantification of ATX.

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates

“…Suppression of the enzymes responsible for defluorination by pre-injecting an extraneous enzyme inhibitor prior to the liable PET ligand has been shown to be viable in reducing bone uptake in both rats and humans in the case of the 5-HT 1A receptor ligand 18 F-CWAY. − However, a preferred approach would be to eliminate the defluorination pathway with minimal modification of the parent structure. Deuterium substitution adjacent to a labile fluorine atom has proven to be an effective means to improve the metabolic stability of both therapeutic candidates − and 18 F-PET tracers. − Accordingly, we synthesized the tetra-deutero analogue ( 19 , 98% d 4 ) with the prediction that the kinetic isotope effect would slow the defluorination metabolic pathway anticipated in 18 . As expected from the bioisosteric nature of H→D exchange, 19 maintained lipophilicity (eLogD) and free brain fraction ( f u,b ) similar to those of 18 .…”