Synthesis of Precursors for Tracers to Image Tumor Hypoxia

Areas of tumors with hypoxia resist successfully chemo- and radiation therapy, unfortunately. Therefore, new tumors often form again after therapy. These could be prevented by a higher radiation dose, if the hypoxic areas could be localised. The research proposal describes improved procedures for known precursors and the synthesis of new ones, which after labelling with [18F]fluorine (or an isotope of iodine) give tracers, which allow to determine such hypoxic areas using positron emission tomography (PET). The most important precursor is a nucleoside from a chemical point of view, derived from 2-nitroimidazole and D-arabinose as carbohydrate. The project addresses three points: a) A new method for glycosidation will be developed, which does not depend on the hitherto used heavy metal salts, especially mercuric cyanide, to couple a protected D-pentose or D-hexose with a silylated 2-nitroimidazole. It will be studied, whether the Vorbrüggen method - trialkylsilyl triflates serve as catalysts for the coupling - can become a viable alternative to the metal-catalysed version. This is especially of importance, if such traces after successful animal tests are evaluated or even used in humans. b) The new method will be used to improve the synthesis of know precursors derived from D-arabinose and to prepare new precursors, which are derived from the anomers of D-ribose, D-2-deoxyribose and D-galactose. Additionally, precursor will be prepared for the first time, which could be enriched in the hypoxic cells by active transport (nucleoside transporters). 2-Nitroimiodazole nucleosides with a free hydroxyl group at C-5 are proposed, which carry the radioactive isotope at C-2, C-3or in a methyl group at C-5 of a D-pentose. The free hydroxyl group at C-5 could be phosphorylated in the cell by a kinase (metabolic trapping). The cold standards of all tracers needed for HPLC will be prepared as well. c) An amino acid based precursor will be prepared as a new type of a precursor to possibly use one of the many amino acid transporters for uptake into the hypoxic cells. The prepared precursors are tested at the ARC (Austrian Research Centre) Seiberdorf (Dr. Angelberger, head of the department of Radiopharmaka) and the Universitätsklinikum Tübingen (Prof. Dr. Machulla, head of the interdisziplinary PET centre) first in animals and in the case of good results in humans, too. These experiments will show whether the tracers can be used routinely in medicine. Letters of recommendation of the two departmental heads are included in the application.

Areas of tumors with hypoxia resist successfully chemo- and radiation therapy, unfortunately. Therefore, new tumors often form again after therapy. These could be prevented by a higher radiation dose, if the hypoxic areas could be localised. The research proposal describes improved procedures for known precursors and the synthesis of new ones, which after labelling with [ 18F]fluorine (or an isotope of iodine) give tracers, which allow to determine such hypoxic areas using positron emission tomography (PET). The most important precursor is a nucleoside from a chemical point of view, derived from 2-nitroimidazole and D-arabinose as carbohydrate. The project addresses three points: 1. A new method for glycosidation will be developed, which does not depend on the hitherto used heavy metal salts, especially mercuric cyanide, to couple a protected D-pentose or D-hexose with a silylated 2- nitroimidazole. It will be studied, whether the Vorbrüggen method - trialkylsilyl triflates serve as catalysts for the coupling - can become a viable alternative to the metal-catalysed version. This is especially of importance, if such traces after successful animal tests are evaluated or even used in humans. 2. The new method will be used to improve the synthesis of know precursors derived from D-arabinose and to prepare new precursors, which are derived from the anomers of D-ribose, D-2-deoxyribose and D-galactose. Additionally, precursor will be prepared for the first time, which could be enriched in the hypoxic cells by active transport (nucleoside transporters). 2-Nitroimiodazole nucleosides with a free hydroxyl group at C-5` are proposed, which carry the radioactive isotope at C-2`, C-3` or in a methyl group at C-5` of a D-pentose. The free hydroxyl group at C-5` could be phosphorylated in the cell by a kinase (metabolic trapping). The cold standards of all tracers needed for HPLC will be prepared as well. 3. An amino acid based precursor will be prepared as a new type of a precursor to possibly use one of the many amino acid transporters for uptake into the hypoxic cells. The prepared precursors are tested at the ARC (Austrian Research Centre) Seiberdorf (Dr. Angelberger, head of the department of Radiopharmaka) and the Universitätsklinikum Tübingen (Prof. Dr. Machulla, head of the interdisziplinary PET centre) first in animals and in the case of good results in humans, too. These experiments will show whether the tracers can be used routinely in medicine. Letters of recommendation of the two departmental heads are included in the application.