Copper-64 based radiopharmaceuticals for brain tumors and hypoxia imaging

The most common and aggressive primary malignancy of the central nervous system is Glioblastoma that, as a wide range of malignant solid tumor, is characterized by extensive hypoxic regions. A great number of PET radiopharmaceuticals have been developed for the identification of hypoxia in solid tumors, among these, we find copper-based tracers. The aim of the current review paper was to provide an overview of radiocopper compounds applied for preclinical and clinical research in brain tumors and hypoxia imaging or therapy.

Copper offers a wide variety of isotopes, useful for nuclear medicine applications, but only ⁶⁴Cu and ⁶⁷Cu are under the spotlight of the scientific community since being good candidates for theranostic applications. Between the two, ⁶⁴Cu availability and production cost have attracted more interest of the scientific community.

In order to better understand the application of copper-bis thiosemicarbazones in hypoxia imaging, an overview of the role of hypoxia in cancer, existing non-imaging and imaging techniques for hypoxia identification and promising future avenues regarding hypoxia is necessary. Different proposed uptake mechanisms of [⁶⁴Cu][Cu(ATSM)] inside the cell will be discussed and other ⁶⁴Cu-based tracers for brain tumors described.

Among radio copper compounds [⁶⁴Cu][Cu(ATSM)] is the most studied radiopharmaceutical for imaging and treatment of brain tumors. Experimental evidence suggested that [⁶⁴Cu][Cu(ATSM)] could be more appropriately considered as a marker of over-reduced intracellular state rather than a pure hypoxia agent. Moreover, preliminary clinical data suggested that [⁶⁴Cu]CuCl2 can be a potentially useful diagnostic agent for malignancies of the central nervous system (CNS).