作者: Brindley, David N. ; Glubrecht, Daryl ; Wuest, Melinda ; Briard, Emmanuelle ; Wuest, Frank ; Litchfield, Marcus ; Auberson, Yves P. ; McMullen, Todd P. W.

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.

2019-08-20·ChemMedChem3区 · 医学

[¹⁸F]PRIMATX, a New Positron Emission Tomography Tracer for Imaging of Autotaxin in Lung Tissue and Tumor‐Bearing Mice

3区 · 医学

Article

作者: Shanmukhappa, Shiva ; Auberson, Yves P. ; Ilovich, Ohad ; Briard, Emmanuelle ; Joshi, Aniket D.

AbstractAutotaxin (ATX) is a secreted enzyme with tissue levels associated with tissue injury, which increase during wound healing and chronic fibrotic diseases. We selected [18F](R,E)‐3‐(4‐chloro‐2‐((5‐methyl‐2H‐tetrazol‐2‐yl)methyl)phenyl)‐1‐(4‐((5‐(2‐fluoroethoxy)pyridin‐2‐yl)methyl)‐2‐methylpiperazin‐1‐yl)prop‐2‐en‐1‐one ([18F]PRIMATX, [18F]2), a tracer for positron emission tomography, to image ATX expression in vivo. It successfully differentiates expression levels in lung tissue samples from idiopathic pulmonary fibrosis patients, and allows the detection of ATX‐expressing tumors in living mice, confirming its potential for development as a clinical imaging agent.

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适应症	最高研发状态	国家/地区	公司	日期
特发性肺纤维化	临床1期	美国	Invicro LLC	2019-07-30
肿瘤	临床前	美国	北京诺华制药有限公司	2019-08-20
肺纤维化	临床前	美国	北京诺华制药有限公司	2019-08-20
特发性肺纤维化	临床前	瑞士	Novartis Pharma AG	2019-07-30
特发性肺纤维化	临床前	美国	Novartis Institutes for Biomedical Research, Inc.	2019-07-30
特发性肺纤维化	临床前	美国	Novartis Pharmaceuticals Corp.	2019-07-30
黑色素瘤	临床前	美国	Invicro LLC	2019-07-30
黑色素瘤	临床前	美国	Novartis Pharmaceuticals Corp.	2019-07-30
黑色素瘤	临床前	美国	Novartis Institutes for Biomedical Research, Inc.	2019-07-30
黑色素瘤	临床前	瑞士	Novartis Pharma AG	2019-07-30