Positron Emission Tomography Imaging of Autotaxin in Thyroid and Breast Cancer Models Using [18F]PRIMATX

• Published in: Molecular pharmaceutics Vol. 18; no. 9; pp. 3352 - 3364
• Main Authors: Litchfield, Marcus, Wuest, Melinda, Glubrecht, Daryl, Briard, Emmanuelle, Auberson, Yves P, McMullen, Todd P. W, Brindley, David N, Wuest, Frank
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 06.09.2021
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cell Line, Tumor; Disease Models, Animal; Female; Fluorine Radioisotopes - administration & dosage; Humans; Male; Mice; Molecular Imaging - methods; Phosphoric Diester Hydrolases - analysis; Phosphoric Diester Hydrolases - metabolism; Positron-Emission Tomography - methods; Radiopharmaceuticals - administration & dosage; Thyroid Neoplasms - drug therapy; Thyroid Neoplasms - pathology; Tissue Distribution; Xenograft Model Antitumor Assays; autotaxin (ATX); fluorine-18; molecular imaging; positron emission tomography (PET); lysophosphatidic acid (LPA)
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00265

Autotaxin (ATX) is a secreted enzyme responsible for producing lysophosphatidic acid (LPA). The ATX/LPA signaling axis is typically activated in wound healing and tissue repair processes. The ATX/LPA axis is highjacked and upregulated in the progression and persistence of several chronic inflammatory diseases, including cancer. As ATX inhibitors are now progressing to clinical testing, innovative diagnostic tools such as positron emission tomography (PET) are needed to measure ATX expression in vivo accurately. The radiotracer, [18F]­PRIMATX, was recently developed and tested for PET imaging of ATX in vivo in a murine melanoma model. The goal of the present work was to further validate [18F]­PRIMATX as a PET imaging agent by analyzing its in vivo metabolic stability and suitability for PET imaging of ATX in models of human 8305C thyroid tumor and murine 4T1 breast cancer. [18F]­PRIMATX displayed favorable metabolic stability in vivo (65% of intact radiotracer after 60 min p.i.) and provided sufficient tumor uptake profiles in both tumor models. Radiotracer uptake could be blocked by 8–12% in 8305C thyroid tumors in the presence of ATX inhibitor AE-32-NZ70 as determined by PET and ex vivo biodistribution analyses. [18F]­PRIMATX also showed high brain uptake, which was reduced by 50% through the administration of ATX inhibitor AE-32-NZ70. [18F]­PRIMATX is a suitable radiotracer for PET imaging of ATX in the brain and peripheral tumor tissues.