| 1976 | Varghese et al. report that the radioactive 2-nitromidazole, 14C-misonidazole, binds to hypoxic mammalian cells. |
| 1981 | Chapman et al. propose 2-nitroimidazoles as companion biomarkers for hypoxia in radiation and chemotherapy. |
| 1986 | Urtasun et al. are first to use a 2-nitroimidazole hypoxia marker (radioactive 3H-misonidazole) in a clinical study of human tumor hypoxia. Dr. James Raleigh invents the non-radioactive, immunochemical 2-nitroimidazole hypoxia marker technique. |
| 1988 | Laurent et al. report the binding of radioactive 14C-pimonidazole in normal and tumor tissue of rats. |
| 1989 | Cline et al. report the first use of the immunochemical 2-nitroimidazole hypoxia marker technique in the clinical setting at the College of Veterinary Medicine, North Carolina State University, Raleigh, NC under the direction of Dr. Donald Thrall. Both immunoperoxidase histochemistry and ELISA detection are used to detect the binding of CCI-103F (Hypoxyprobe-F6). |
| 1992 | The first patent is issued to Dr. Raleigh for the immunochemical detection of tissue hypoxia by means of antibodies that recognize adducts of 2-nitroimidazoles in hypoxic tissues. |
| 1993 | Dr. Mahesh Varia, UNC Chapel Hill, receives clearance from the FDA for the use of intravenous pimonidazole HCl as an Investigational New Drug for the immunochemical detection of hypoxia in humans. |
| 1995 | Arteel et al. report the first use of pimonidazole HCl as an immunochemical hypoxia marker in normal tissue. Both immunoperoxidase histochemistry and ELISA are used. Hypoxyprobe Division of Natural Pharmacia International, Inc. makes pimonidazole HCl widely available for animal and clinical studies. |
| 1997 | Kennedy et al. (UNC Chapel Hill) are first to use pimonidazole binding in a clinical study of human tumor hypoxia. |
| 1998 | Raleigh et al. report the first clinical study in which pimonidazole binding is compared with the expression of an oxygen-regulated protein (VEGF). The study is carried out with squamous cell carcinoma of the uterine cervix at UNC Chapel Hill. |
| 1999 | Raleigh et al. report that pimonidazole binding is highly correlated with oxygen electrode measurements and radiation response in murine tumors. |
| 2000 | Wijffels et al. (University Medical Center Nijmegen, The Netherlands) are first to use pimonidazole HCl as an immunochemical hypoxia marker in European clinical studies. |
| 2002 | Kaanders et al. (University Medical Center Nijmegen, The Netherlands) perform the first clinical comparison between pimonidazole binding and radiation response in human patients undergoing hypoxia dependent radiation therapy (ARCON). |
| 2006 | Mahesh Varia, MD at UNC Chapel Hill receives clearance from the FDA for the use of oral pimonidazole HCl as an Investigational New Drug for the immunochemical detection of hypoxia in humans. Kleiter et al. are first to use of oral pimonidazole HCl as a hypoxia marker in spontaneous tumors in the clinical setting of the College of Veterinary Medicine, North Carolina State University under the direction of Dr. Donald Thrall. |
| 2008 | Threshold Pharmaceuticals adopts pimonidazole HCl as an immunochemical hypoxia marker in preclinical and clinical studies of their anti-cancer, hypoxia-activated prodrug, TH302. |
| 2009 | Varia et al. (UNC Chapel Hill) report the first use of oral pimonidazole HCl as a clinical immunochemical hypoxia marker. |
| 2012 | Oral administration of pimonidazole HCl is in clinical use in the US, Canada and Norway. Kaanders et al. publishes the first randomized Phase III study of pimonidazole binding as a marker for hypoxia in patients undergoing hypoxia dependent radiation therapy (ARCON). A literature search reveals 549 publications in which pimonidazole HCl is used as a immunochemical hypoxia marker -- 70 of these publications arise from clinical studies. |