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

Area of Science:

• Biochemistry
• Radiochemistry
• Molecular Imaging

Background:

• Autotaxin (ATX) is a key enzyme in various pathologies, including fibrosis and cancer.
• Current ATX inhibitors lack a validated positron emission tomography (PET) probe for in vivo studies.
• Developing a specific PET radioligand is crucial for understanding ATX's role in disease progression.

Purpose of the Study:

• To synthesize and evaluate novel fluorinated imidazo[1,2-a]pyridine derivatives as potential ATX-targeted PET radioligands.
• To identify a stable and effective PET tracer for non-invasive ATX quantification.
• To assess the utility of the developed PET probe in a preclinical model of liver injury.

Main Methods:

• Synthesis of a focused library of fluorinated imidazo[1,2-a]pyridine derivatives.
• Determination of inhibition constants (Ki) and confirmation of binding modes via crystallographic analysis.
• Radiofluorination of promising compounds and evaluation of in vitro and in vivo stability, including a deuterated analog ([18F]ATX-1905).

Main Results:

• Several compounds demonstrated potent ATX inhibition.
• [18F]ATX-1905 exhibited superior in vivo stability against radiodefluorination compared to other radiofluorinated analogs.
• In vitro and in vivo studies in a mouse model of LPS-induced liver injury supported the utility of [18F]ATX-1905.

Conclusions:

• [18F]ATX-1905 is a highly stable and promising PET radioligand for targeting autotaxin.
• This novel tracer enables non-invasive quantification of ATX, potentially aiding in the diagnosis and monitoring of ATX-related pathologies.
• The developed PET probe offers a valuable tool for future research in fibrosis, cancer, and other ATX-implicated diseases.