Technologies

The University of Texas at Dallas is seeking companies interested in commercializing novel paramagnetic shift imaging reagents that enable discrimination of D- versus L-lactate - the unique metabolic hallmarks that distinguish cancerous tumors from benign growths and normal tissues.

In the past, the development of non-invasive differential diagnostic methods of tumor analysis has been hindered by the inability to discriminate between these key enantiomeric forms of lactate. UTD presents its novel reagents and the associated methodology for cancer diagnosis which have been demonstrated in an animal model through imaging excess lactate excreted into the bladder of a mouse.

The invention presented here takes advantages of several newly synthesized novel paramagnetic shift reagents (SR) which form selective, stable complexes with either D- or L-lactate. It has been known that cancer cells can excrete D-lactate while healthy mammalian cells only produce L-lactate. These complexes shift the lactate –OH proton resonance far away from the water while retaining the chemical exchange saturation transfer (CEST) properties of lactate itself. The magnified chemical shift of lactate complexes effectively separates them from the water signals. More importantly and significantly, these D- and L-lactate complexes generate a sufficient difference in chemical shifts between each structure that allows for enantiomeric discrimination by CEST-MRI. Given that the development of enantio-pure agents is of great interest in molecular imaging, this work is a positive advancement towards optimizing inorganic shift reagents for selective identification of important biomarkers and metabolic profiles.

Technical Summary:

The novel paramagnetic shift imaging contrast reagents, Yb ₁ through Yb ₄ , are synthesized in a 9-step procedure. They are applied in an assay to quantify the ratios of both lactate isomers through CEST-MRI. These reagents do not discriminate between the two enantiomeric forms of lactate by forming a stable complex with either D- or L-lactate. All complexes have virtually identical molecular geometries. However, they have different chemical shifts due to the different position of the lactate proton nuclei with respect to the magnetic properties of the Yb ion. Since each agent has only one stereoisomer and forms a stable complex with either lactate isomer, they are able to provide a stronger signal than commercial contrast reagents used for this purpose, such as EuDO3A. Overall, the proton exchange rates were close to optimal at 310 K, beneficial for experiments performed at physiological temperatures. The Yb ₃ demonstrated especially strong chemical stability at various pH conditions and was further shown to be stable in severalin vivomodels.