Neutral 99m Tc(CO) 3 complexes of ‘‘clicked’’ nitroimidazoles for the detection of tumor hypoxia Mohini Bhadwal 1 • Madhava B. Mallia 1 • Haladhar Dev Sarma 2 • Sharmila Banerjee 1 Received: 25 November 2014 Ó Akade ´miai Kiado ´, Budapest, Hungary 2015 Abstract In the present work, three neutral 99m Tc(CO) 3 complexes of nitroimidazole were synthesized and their potential to detect tumor hypoxia is evaluated in vivo. Triazole derivatives of 2-, 4- and 5-nitroimidazole were synthesized via ‘click chemistry’ route. The ligands syn- thesized were characterized and subsequently radiolabeled using [ 99m Tc(CO) 3 (H 2 O) 3 ] ? precursor complex to obtain corresponding neutral 99m Tc(CO) 3 complexes in [ 90 % radio chemical purity. The complexes were subsequently evaluated in Swiss mice bearing fibrosarcoma tumor and in vivo distribution observed was thoroughly analyzed. All complexes showed uptake in tumor, however, contrary to general expectations, the 5-nitroimidazole complex showed significantly higher tumor uptake (p \ 0.05) at 30 min and 60 min p.i., compared to the 2-nitroimidazole counterpart. Though a conclusive explanation for this observation could not be obtained, present study underlined the significance of evaluating nitroimidazole radiotracers other than 2-ni- troimidazole for detecting tissue hypoxia. Keywords Hypoxia Á Nitroimidazole Á [ 99m Tc(CO) 3 (H 2 O) 3 ] ? precursor complex Á Click- chemistry Á Neutral complexes Á Biodistribution Introduction The negative influence of hypoxia in the clinical manage- ment of cancer is well documented [1–9]. Information on hypoxic status of cancerous lesion can help in patient se- lection for hypoxia directed treatment and to bring appro- priate alterations to treatment strategy for a better clinical outcome [1]. Nitroimidazoles which show selective accu- mulation in hypoxic cells are the most widely explored molecules for delineating hypoxic tumor cells from nor- moxic cells [10]. Several nitroimidazole radiopharmaceu- ticals based on PET as well as SPECT isotopes are reported [11–28]. Presently, [ 18 F]fluoromisonidazole ([ 18 F]FMISO), a 2-nitroimidazole-radiotracer, is the radiopharmaceutical of choice for clinical imaging of tumor hypoxia [29]. However, owing to optimal decay characteristics, easy availability and low cost of 99m Tc, a nitroimidazole ra- diopharmaceutical based on this isotope may find wider applicability. Though, several 99m Tc-labeled nitroimida- zole radiopharmaceuticals are evaluated for detecting tu- mor hypoxia, 99m Tc-BRU59-21 is, probably, the only complex that reached phase-I clinical trials [30]. Other complexes evaluated so far have not shown suitable phar- macokinetics for hypoxia detecting applications in a clin- ical setup. This aspect has provided the impetus for the development of new nitroimidazole radiopharmaceuticals labeled with 99m Tc for targeting tumor hypoxia. Introduction of unconventional 99m Tc-cores, such as [ 99m TcN] ?2 core and [ 99m Tc(CO) 3 ] ? core, for radiolabeling biomolecules have alleviated the problems associated with the usage of the conventional 99m Tc-oxo or 99m Tc-dioxo cores to a great extent. The [ 99m TcN] ?2 core and [ 99m Tc(CO) 3 ] ? core are easy to prepare and stable over a wide range of pH conditions. The [ 99m Tc(CO) 3 (H 2 O) 3 ] ? precursor complex, introduced by Alberto et al., is Electronic supplementary material The online version of this article (doi:10.1007/s10967-015-4135-0) contains supplementary material, which is available to authorized users. & Sharmila Banerjee sharmila@barc.gov.in 1 Radiopharmaceuticals Chemistry Section, Bhabha Atomic Research Centre, Mumbai 400085, India 2 Radiation Biology and Health Sciences Division, Bhabha Atomic Research Centre, Mumbai 400085, India 123 J Radioanal Nucl Chem DOI 10.1007/s10967-015-4135-0