Radiolabeled probes for tumor hypoxia imaging

The hypoxic microenvironment within tumors serves as a pivotal factor that propels malignant progression and fosters resistance to both radiotherapy and chemotherapy. Therefore, non-invasive hypoxia imaging using radionuclides is crucial for establishing personalized treatment plans. This review summarizes research progress on various radiolabeled hypoxia imaging probes. It focuses on bioreductive nitroimidazole derivatives, metal complexes, novel molecules targeting hypoxia-induced proteins (such as CA IX), and dual-targeting probes. The review elucidates the relationship between probe structural design and in vivo imaging performance. The development of probes has transitioned from an initial emphasis on high lipophilicity and uptake (e.g., [¹⁸F]FMISO) to a novel phase centered on hydrophilic modifications, including glycosylation and PEGylation. These modifications optimize pharmacokinetics and improve the signal-to-noise ratio. This review details the impact of various strategies on probe uptake in tumor and non-target tissues. These strategies encompass the nitroimidazole positional isomer effect, particularly highlighting the benefits of the 2-position, along with multivalent implementations. They also include the precise regulation of linker types and lengths, the selection of radionuclide chelators, and molecular charge adjustment. Furthermore, a comparative analysis elucidates the pivotal function of "fine-tuning the redox potential" in augmenting specificity. Modifying probes by incorporating electron-donating groups moderately decreases their reduction potential. This strategy effectively reduces non-specific background signals and achieves an optimal redox potential window. Finally, this review provides a concise summary of the existing challenges associated with hypoxia-targeting probes and puts forth innovative concepts for their future development. Ideal probe design should aim for the precise synergy of "appropriate pharmacokinetics", "optimal redox potential", and dual-targeting or multi-targeting strategies. These methodologies furnish a theoretical foundation and design concepts for the forthcoming generation of tumor hypoxia imaging agents.