Synthesis of a 2-nitroimidazole glycopeptide radiolabeled with (68)Ga for positron emission tomography (PET) imaging of tumor hypoxia

Abstract

Hypoxia is a pathological condition characterized by a reduction of oxygen supply to a specific tissue or cell. About 60% of solid tumors in an advanced stage present areas of hypoxia. Tumor-associated hypoxia has been correlated to: 1) tumor aggressiveness; 2) resistance to chemotherapy and radiotherapy; 3) poor prognosis. Thus, the use of non-invasive methods dedicated to assess tumor hypoxic areas are of extremely importance for the treatment of several types of cancers, allowing the use of individualized therapeutic strategies. Here, we developed a new 68Ga-labeled radiopharmaceutical for positron emission tomography (PET) imaging of tumor hypoxia. The 68Ga-labelled 2-nitroimidazole derivative was successfully obtained by linking the 2- nitroimidazole acetic acid derivative with a glycopeptide obtained by solid phase synthesis and further conjugated to DOTA-NHS and its identity was confirmed by mass spectrometry. The radiolabeling procedure of 68Ga-Glycopeptide was optimized regarding the amount of glycopeptide, temperature and time, and was obtained with a high radiochemical purity (96.6± 0.4%). Compared to the standard hypoxic radiopharmaceutical 18 68 F-FAZA, Cancer is a chronic degenerative process that culminates in the loss of mechanisms that regulate cell cycle and death. In addition, it is considered a public health problem worldwide and its incidence has grown by 20% in the last decade. In Brazil, it is the second cause of death due to illness and the National Cancer Institute estimate is approximately 600 thousand Ga-Glycopeptide was obtained in a faster way and high radiochemical purity was achieved after radiolabeling procedures. Our new 68Ga-Glycopeptide may be promising candidate for further evaluation as a potential hypoxia imaging agent. Moreover, the use of 68Ga as an alternative to 18F in the development of new tracers for PET imaging is still an advantage because of the use of radionuclide generators instead of costly cyclotron equipment. Additionally, the use of a glycopeptide may allow the development of a kit-type setup that will ease the preparation of the 68Ga-based agent.