WEAKLY BASIC 2- NITROIMIDAZOLES FOR THE NON-INVASIVE DETECTION OF TISSUE HYPOXIA

摘要

The present invention incorporates weakly basic substituents (pKa about 8 or greater) such as pyrrolidine, piperidine, piperazine and azapane moietie s in halogenated 2-nitromidazoles as a major improvement over prior art for the non-invasive detection of cellular hypoxia in normal and malignant tissu es. The invention features the use of [18F] positron emission tomography, [1 9F] magnetic resonance spectroscopy, and [19F] magnetic resonance imaging. I mprovements over prior art compounds are six-fold. 1) Salts of weakly basic reagents are highly water-soluble which facilitates administration. 2) Unrea cted reagents are rapidly cleared from systemic circulation thereby decreasi ng background noise. 3) Reagents with weakly basic substituents are concentr ated in tissue ~ 3 fold above plasma levels thereby increasing binding inten sity and enhancing signal detection. 4) Conjugate bases of weakly basic reag ents have intermediate octanol-water partition coefficients that facilitate their penetration into all tissues including brain. 5) Cellular adducts of r eagents containing weakly basic substituents are more stable than reagents o f prior art. 6) Reagents with weakly basic substituents are effective for th e detection of transient hypoxia in solid tissue.