Synthesis and experimental study of norfloxacin labeled with technecium-99m as a potential agent for infection imaging

Document Type : Original Article


1 Research Institute of Cardiology of the Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russia AND National Research Tomsk Polytechnic University, Tomsk, Russia 3Siberian State Medical University, Tomsk, Russia

2 Research Institute of Cardiology of the Siberian Branch of the Russian Academy of Medical Sciences, Tomsk, Russia

3 National Research Tomsk Polytechnic University, Tomsk, Russia

4 Siberian State Medical University, Tomsk, Russia


Introduction: Differentiation between infection and sterile inflammation is one of the most difficult medical problems and is relevant in many clinical situations. Scintigraphy with radiolabeled antibiotics, еspecially labeled fluoroquinolones, is a promising tool for diagnosing bacterial inflammation. We have attempted to synthesize 99mTc-norfloxacin and studied its properties in experiment. Methods: In present study we labeled norfloxacin with 99mTc, determined its radiochemical purity by thin-layer chromatography procedure, compared the bactericidal activity of 99mTc-norfloxacin and unlabelled norfloxacin by disk diffusion, performed in vitro binding assays and evaluated the feasibility of 99mTc-norfloxacin to image soft-tissue infections in rat modal of thigh muscle infection. Scintigraphy was performed at 30 min, 90 min and 18 h post injection. Abscess –to–normal-site ratios were calculated. Results: In this study 99mTc-norfloxacin with high radiochemical purity and low colloid content was synthesized. Disk diffusion method showed that 99mTc-norfloxacin retains bactericidal properties of unlabelled norfloxacin. In vitro binding studies demonstrated small degree of the tracer binding with S. aureus and ability of 99mTc-norfloxacin to bind with killed as well as alive bacteria. Uptake of the tracer was clearly visible in infected muscles and not visible in sterile inflammed muscles. Conclusion: The 99mTc-norfloxacin retains bactericidal properties of unlabelled norfloxacin. The tracer demonstrated small degree of S. aureus binding both with killed as well as alive bacteria. Studies which were performed in vivo in rats with a model of thigh muscle infection showed good ability of the radiopharmaceutical to image the infection.


Main Subjects

Petruzzi N, Shanthly N, Thakur M. Recent trends in soft-tissue infection imaging. Semin Nucl Med. 2009 Mar;39(2):115-23.
Britton KE, Vinjamuri S, Hall AV, Solanki K, Siraj QH, Bomanji J, Das S. Clinical evaluation of technetium-99m infecton for the localisation of bacterial infection. Eur J Nucl Med. 1997 May;24(5):553-6.
Dumarey N, Blocklet D, Appelboom T, Tant L, Schoutens A. Infecton is not specific for bacterial osteo-articular infective pathology. Eur J Nucl Med Mol Imaging. 2002 Apr;29(4):530-5.
Pucar D, Janković Z, Dugonjić S, Popović Z. Estimation of 99mTc-ciprofloxacin accumulation indexes in bone and joint bacterial infections. Vojnosanit Pregl. 2009 May;66(5):395-8.
Sarda L, Saleh-Mghir A, Peker C, Meulemans A, Crémieux AC, Le Guludec D. Evaluation of (99m)Tc-ciprofloxacin scintigraphy in a rabbit model of Staphylococcus aureus prosthetic joint infection. J Nucl Med. 2002 Feb;43(2):239-45.
Sonmezoglu K, Sonmezoglu M, Halac M, Akgün I, Türkmen C, Onsel C, Kanmaz B, Solanki K, Britton KE, Uslu I. Usefulness of 99mTc-ciprofloxacin (infecton) scan in diagnosis of chronic orthopedic infections: comparative study with 99mTc-HMPAO leukocyte scintigraphy.  J Nucl Med. 2001 Apr;42(4):567-74.
Skuridin VS, Varlamova NV, Belyanin ML, Sazonova SI, Konkovskaya YN, Takhauov RM: Synthesis and biological characterization of 99mTc-labeled ciprofloxacin. Pharm Chem J. 2009; 43(9): 516-20.
Ibrahim IT, Motaleb MA, Attalah KM. Synthesis and biological distribution of 99mTc–norfloxacin complex, a novel agent for detecting sites of infection. J Radioanal Nucl Chem. 2010;285:431-36.
Zhang S, Zhang W, Wang Y, Jin Z, Wang X, Zhang J, Zhang Y. Synthesis and biodistribution of a novel (⁹⁹m)TcN complex of norfloxacin dithiocarbamate as a potential agent for bacterial infection imaging. Bioconjug Chem. 2011 Mar 16;22(3):369-75.
Nayak DK, Baishya R, Halder KK, Sen T, Sarkar BR, Ganguly S, Das MK, Debnath MC.  Evaluation of (99m)Tc(i)-tricarbonyl complexes of fluoroquinolones for targeting bacterial infection. Metallomics. 2012 Nov;4(11):1197-208.
Erfani M, Doroudi A, Hadisi L, Andishmand A, Mirshojaei SF, Shafiei M.  (99m) Tc-tricabonyl labeling of ofloxacin and its biological evaluation in Staphylococcus aureus as an infection imaging agent. J Labelled Comp Radiopharm. 2013 Oct;56(12):627-31.
Varlamova NV, Skuridin VS, Sazonova SI. Preparation and medical and biological testing of 99mTc-norfloxacin. Bull Siberian Med. 2010; 9(6):108-15.
Mokrushina GA, Kotovskaya SK, Baskakova ZM, Petrova GM, Kolmakova TV, Charushin VN, Rusinov VL, Chupakhin ON. Improved method for the synthesis of norfloxacin. Pharm Chem J. 1996;30(8): 540-42.
Titov IV, Dorofeev VL, Arzamastsev AP. The Use of UV-Spectrometry method to authenticate fluoroquinolone drugs. Vestn VGU(Ser: Khim Biol Farm)2004;2:264-69.
Rahman A, Hossain MA, Paul SK, Sultana S, Haque N, Kabir MR, Hoque SM. Methicillin-resistant coagulase-negative staphylococci (MRCoNS) by disk diffusion method. Mymensingh Med J. 2013 Apr;22(2):229-31.
Yakovlev VP. Fluoroquinolone. Consilium Medicum. 2006; 8(1):35-41.
Sierra JM, Rodriguez-Puig D, Soriano A, Mensa J, Piera C, Vila J. Accumulation of 99mTc-ciprofloxacin in Staphylococcus aureus and Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2008 Jul;52(7):2691-2.
Alexander K, Drost WT, Mattoon JS, Kowalski JJ, Funk JA, Crabtree AC. Binding of ciprofloxacin labelled with technetium Tc 99m versus 99mTc-pertechnetate to a live and killed equine isolate of Escherichia coil. Can J Vet Res. 2005 Oct;69(4):272-7.