Synthesis and Evaluation of 4-Bromo-1-(3-[18F]fluoropropyl)-2-nitroimidazole with a Low Energy LUMO Orbital Designed as Brain Hypoxia-Targeting Imaging Agent.

Abstract

2-Nitroimidazole derivatives typified by misonidazole (MISO), originally developed as hypoxic radiosensitizers for radiation therapy, have been shown to be susceptible to reduction trapping in regions of low oxygen tension. Although the mechanism of nitroimidazole binding to hypoxic tissue is still not fully understood, the nitro group is believed to undergo a one-electron reduction in viable cells to produce a radical anion, while in hypoxic cells this intermediate is further reduced to a species which reacts with cellular components and is hereby trapped within the cell. In normoxic conditions reoxidation rapidly takes place, and the compound eventually diffuses out of the cell.1-3) This is the why most efforts to develop selective markers for imaging hypoxic tissue have used 2-nitroimidazole derivatives. 4)18 F-Labeled fluoromisonidazole ( 18 FMISO) has shown potential in humans as an agent to map hypoxic tissue with positron emission tomography (PET). [5][6][7][8] However, this agent has drawbacks due to its relatively low concentration within hypoxic tissue and the necessity to wait a long time (2-4 h) to achieve acceptable target-background ratios for imaging. The target tissues have mostly been the myocardium or tumors, with less attention centered on the brain. The utility of 18 FMISO as a hypoxic imaging agent for brain studies appears to be limited because of its low blood-brain barrier (BBB) permeability. 9,10) We have been interested in the development of new PET markers exhibiting more rapid localization in the hypoxic region in the brain with a greater BBB permeability than 18 FMISO, based on the same principle of metabolic binding of nitroreduction products. In a previous paper, we reported the synthesis and evaluation of the two lipophilic 2-nitroimidazoles, 1-(3-[ 11) The high lipophilicity of 18 FPN and 18 FON resulted in the increased initial uptake into normal rat brain, relative to 18 FMISO, but both compounds had significantly lower tumor uptake and lower tumor-toblood ratios than 18 FMISO, suggestive of a poor trapping mechanism within the tumor tissue. One of the primary reasons for these disappointing results appeared to be the lack of a sufficiently high reduction potential (electron affinity) undergoing more rapid bioreduction of the nitro group. Therefore, we have now designed 4-bromo-1-(3-fluoropropyl)-2-nitroimidazle (4-BrFPN), based on the molecular orbital calculations, to improve the electron affinic property of the 2-nitroimidazole ring, with sufficient lipophilicity to penetrate the BBB to image cerebral hypoxia. In this paper we describe the design, synthesis and radiolabeling with fluorine-18 of 4-BrFPN. Additionally, the in vivo biodistribution of this designed compound is also characterized in normal rats and in tumor-bearing mice to evaluate its potential use as a marker of hypoxic tissue in comparison with 18 FMISO and 18 FPN. RESULTS AND DISCUSSIONDesign Reduction potential, as well as lipophilicity, is considered important in the rational design of hypoxia-selec- * To w...

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