Radiopharmaceuticals in Tumor Hypoxia Imaging: A Review Focused on Medicinal Chemistry Aspects

Since its first description in 1955, tumor hypoxia has become a central issue in cancer treatment. Since then, it is essential to diagnose accurately the tumor oxygenation degree in order to establish the appropriate treatment. In this regard, a wide diversity of radiopharmaceuticals for in vivo imaging has been developed. Special conditions of the hypoxic microenvironment are low O2 partial pressure, enhanced levels of reductases, and genetic-adaptation-expression biomolecules involved in angiogenesis, erythropoiesis, cellular proliferation, apoptosis, metabolism- and glucose-uptake, local invasion, and metastatic spread. The development of radiolabeled hypoxia markers has been based on reductase substrates, like bioreductive ligands, or on entities capable of recognizing overexpressed proteins under hypoxia conditions, i.e. HIF-1α and carbonic anhydrase IX, among others. In this review these hypoxia markers are analyzed focusing on their medicinal chemistry characteristics.