Imaging Hypoxia by Novel Chemical Reagents

Abstract

Bio-responsive probes are the latest development of radiopharmaceuticals. They are responsible for the treatment, diagnosis, and monitoring of the therapy for many ailments. Nitroimidazole and its derivatives have been used in imaging for a long time. The chemistry of nitroimidazole derivatives suggest that they have an affinity towards electrons, which means they are really reduced them when they react with suitable enzymes. 2-Methyl-5-nitro-1-(oxiran-2-ylmethyl)-1H-imidazole (the epoxide derived from ornidazole) is one of the impurities present in the ornidazole and is categorized in the pharmacopoeial reference standards (PhRSs). The synthesis of the epoxide of ornidazole epoxide includes a cyclization process of the side chain of ornidazole. Reaction of epoxide compounds with amine group containing compounds takes place, by opening of the epoxide ring and formation of aminoalcohol. The addition reaction of a thiol to an epoxide containing compounds is may be categorized under click chemistry, which takes place under mild conditions. This research was undertaken to synthesize derivative of 5-nitroimidazole, which can be prospective molecules for creating bioresponsive probes for diagnosis of hypoxia. The initial step was to synthesize the epoxide of ornidazole under basic conditions. This compound was characterized using Nuclear Magnetic Resonance (NMR) spectroscopy, mass spectroscopy and Infrared spectroscopy. Ornidazole epoxide was then used for synthesizing respective amino-alcohol and thiol derivatives by reaction process optimization. The isolated derivatives were also characterized using NMR spectroscopy and mass spectroscopy. The log P of the synthesized derivatives were also be compared with the log P of epoxide compound. The results suggest that Ornidazole epoxide was synthesized successfully. The reaction of epoxide and dopamine HCl was of limited success under the investigated reaction conditions. 1H NMR suggested mostly starting materials although MS data suggested small amounts of product were present. 1H NMR data of the thiol derivatives showed that reaction of epoxide compound and 1-dodecacanethiol, and epoxide and 1-decanethiol were successful to certain extent and showed formation of desired thiol derivatives.