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Design, Preparation, and Evaluation of a Novel 99Mtcn Complex of Ciprofloxacin Xanthate As a Potential Bacterial Infection Imaging Agent

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Design, Preparation, and Evaluation of a Novel 99Mtcn Complex of Ciprofloxacin Xanthate As a Potential Bacterial Infection Imaging Agent molecules Article Design, Preparation, and Evaluation of a Novel 99mTcN Complex of Ciprofloxacin Xanthate as a Potential Bacterial Infection Imaging Agent Si’an Fang, Yuhao Jiang, Qianqian Gan, Qing Ruan, Di Xiao and Junbo Zhang * Key Laboratory of Radiopharmaceuticals, Ministry of Education, College of Chemistry, Beijing Normal University, Beijing 100875, China; [email protected] (S.F.); [email protected] (Y.J.); [email protected] (Q.G.); [email protected] (Q.R.); [email protected] (D.X.) * Correspondence: [email protected]; Tel.: +86-10-6220-8126 Academic Editor: Rodica Olar Received: 31 October 2020; Accepted: 7 December 2020; Published: 10 December 2020 Abstract: In order to seek novel technetium-99m bacterial infection imaging agents, a ciprofloxacin xanthate (CPF2XT) was synthesized and radiolabeled with [99mTcN]2+ core to obtain the 99mTcN-CPF2XT complex, which exhibited high radiochemical purity, hydrophilicity, and good stability in vitro. The bacteria binding assay indicated that 99mTcN-CPF2XT had specificity to bacteria. A study of biodistribution in mice showed that 99mTcN-CPF2XT had a higher uptake in bacterial infection tissues than in turpentine-induced abscesses, indicating that it could distinguish bacterial infection from sterile inflammation. Compared to 99mTcN-CPFXDTC, the abscess/blood and abscess/muscle ratios of 99mTcN-CPF2XT were higher and the uptakes of 99mTcN-CPF2XT in the liver and lung were obviously decreased. The results suggested that 99mTcN-CPF2XT would be a potential bacterial infection imaging agent. Keywords: ciprofloxacin xanthate; quinolones; infection imaging; 99mTc-radiolabeling 1. Introduction Public health advanced during the eighteenth and nineteenth centuries and with antibiotics discovered in the twentieth century, treatment of infection has been highly improved. However, at present, antibiotic abuse has led to the emergence of bacteria resistance, which limits the efficiency of antibiotics. Bacterial infection is one of the most common causes of morbidity and mortality in developing countries [1]. In the meantime, it is predicted that infections of antibiotic resistance would be the first cause of human death by 2050 [2]. Considering the patients carrying inflammation may have different disease processes occurring at the same time, the clinic assessments do not always find a clear pathogen, which leads to delay in treatment and antibiotic abuse. In that case, early detection of infections can allow for the timely and appropriate treatment of patients, avoiding the overuse of antibiotics [3]. Identifying and locating lesion sites of infection is a critical step in clinic treatment. Computed tomography (CT) and magnetic resonance imaging (MRI) are available for detecting infections. However, these imaging tools depend on anatomical changes that occur late in the disease process, so that in the early phase, they detect the infection foci inefficiently because obviously morphologic changes cannot be observed [4]. Compared to CT and MRI, nuclear medicine techniques such as Positron Emission Tomography (PET) and Single-Photon Emission Computed Tomography (SPECT) are based on physiochemical and biochemical changes in organs, which will be located in the early phase. Radiopharmaceuticals with high specificity can selectively concentrate at the site Molecules 2020, 25, 5837; doi:10.3390/molecules25245837 www.mdpi.com/journal/molecules Molecules 2020, 25, 5837 2 of 9 Molecules 2020, 25, x FOR PEER REVIEW 2 of 9 of infection, which leads to accurate detection of pathogens, and the rapid and suitable treatment phase. Radiopharmaceuticals with high specificity can selectively concentrate at the site of infection, of patients [1]. Currently, discriminating between infection and sterile inflammation has been of which leads to accurate detection of pathogens, and the rapid and suitable treatment of patients [1]. great significance. Various radiopharmaceuticals have been developed for detecting inflammation Currently, discriminating between infection and sterile inflammation has been of great significance. in humans, however, they have some limitations [5]. The development of new infection imaging Various radiopharmaceuticals have been developed for detecting inflammation in humans, however, radiopharmaceuticals is still needed in nuclear medicine. they have some limitations [5]. The development of new infection imaging radiopharmaceuticals is stillTechnetium-99m needed in nuclear is extensivelymedicine. used in nuclear medicine, which is due to its in-house availability, low cost,Technetium-99m decay characteristics, is extensively and used the in ability nuclear to medicine, conjugate which with is bioactive due to its in-house molecules availability, through a 99m bifunctionallow cost, decay chelator characteristics, [6]. Up tonow, and therethe ability have to been conjugate several with kinds bioactive of Tc-labeled molecules antimicrobial through a 99m agentsbifunctional [7–11]. Amongchelator them,[6]. Up to Tc-ciprofloxacinnow, there have hasbeen been several widely kinds evaluated of 99mTc-labeled by many antimicrobial groups in the 99m worldagents [12 [7–11].,13]. Compared Among them, to the 99m radiolabeledTc-ciprofloxacin leucocytes has been [14 widely], Tc-ciprofloxacin evaluated by many has moregroups specificity in the forworld infection, [12,13]. lower Compared cost of preparation,to the radiolabeled better leucocytes imaging quality, [14], 99mTc-ciprofloxacin and it can be prepared has more from specificity a kit [15 ]. However,for infection, there lower are somecost of limitations preparation, of better99mTc-ciprofloxacin, imaging quality, and such it ascan low be prepared radiochemical from a yieldkit [15]. and heatingHowever, preparation there are [ 16some]. In limitations the structure of 99m ofTc-ciprofloxacin, ciprofloxacin, thesuch carbonyl as low radiochemical and carboxyl yield groups and are consideredheating preparation as necessary [16]. pharmacophores, In the structure which of ciprofloxacin, possibly coordinate the carbonyl with and technetium-99m, carboxyl groups therefore, are labelingconsidered with as99m necessaryTc would pharmacophores, reduce the binding which affi possinitybly to bacteria coordinate [17 with]. technetium-99m, therefore, labeling[99mTcN] with2+ 99mcoreTc would was reduce found the to binding conjugate affinity well to with bacteria ligands [17]. containing S atoms, such as dithiocarbamates[99mTcN]2+ core [18]. was Recently, found ourto conjugate group has well developed with ligands some 99mcontainingTc-labeled S atoms, antibiotic such tracers. as 99m Fordithiocarbamates example, we synthesized [18]. Recently, ciprofloxacin our group dithiocarbamatehas developed some (CPFXDTC, Tc-labeled as shownantibiotic in Figuretracers.1 )For and radiolabeledexample, we it with synthesized [99mTcN] 2ciprofloxacin+ core. 99mTcN-CPFXDTC dithiocarbamate was (CPFXDTC, easily prepared as shown through in a ligand-exchangeFigure 1) and radiolabeled it with [99mTcN]2+ core. 99mTcN-CPFXDTC was easily prepared through a ligand- reaction. In the biodistribution assay in bacteria-infected mice, the infection uptake was 3.21 0.66% exchange reaction. In the biodistribution assay in bacteria-infected mice, the infection uptake± was ID/g at 4 h post-injection. The abscess/muscle and abscess/blood ratios were 1.78 and 1.86. Compared to 3.21 ± 0.66% ID/g at 4 h post-injection. The abscess/muscle and abscess/blood ratios were 1.78 and 99mTc-ciprofloxacin, the abscess uptake and abscess/blood ratio were higher, but the abscess/muscle 1.86. Compared to 99mTc-ciprofloxacin, the abscess uptake and abscess/blood ratio were higher, but ratio was much lower. In addition, 99mTcN-CPFXDTC was lipophilic so the higher accumulation of the abscess/muscle ratio was much lower. In addition, 99mTcN-CPFXDTC was lipophilic so the higher radioactivity was found in the liver. The lung uptake was appreciable as well [18]. These limitations accumulation of radioactivity was found in the liver. The lung uptake was appreciable as well [18]. couldThese aff limitationsect the quality could affect of infection the quality imaging. of infection Therefore, imaging. Therefore, further research further research is needed is needed to solve theseto solve problems. these problems. (a) (b) Figure 1. Chemical structures of CPFXDTC and CPF2XT: (a) ciprofloxacin dithiocarbamate, CPFXDTC; Figure 1. Chemical structures of CPFXDTC and CPF2XT: (a) ciprofloxacin dithiocarbamate, (b)CPFXDTC; ciprofloxacin (b) ciprofloxacin xanthate. xanthate. AsAs xanthate xanthate containscontains two sulfur sulfur atoms atoms and and can can be easily be easily labeled labeled with withtechnetium-99m, technetium-99m, our ourgroup group has has recently recently reported reported some some radiolabeled radiolabeled xanthates xanthates as potential as potential imaging imaging agents [19,20]. agents These [19,20 ]. Thesebackgrounds backgrounds encourage encourage us to ussynthe to synthesizesize a ciprofloxacin a ciprofloxacin xanthate xanthate (CPF2XT, (CPF2XT, as shown as shown in Figure in Figure1) and 1) 99m andevaluate evaluate the the possibility possibility of 99m ofTcN-CPF2XTTcN-CPF2XT as a potential as a potential bacterial bacterial infection infection imaging imaging agent. agent. 2. Results 2.1. Synthesis The reaction equation was shown in Scheme1. CPF2XT was prepared by reacting the precursor N40-2-hydroxyethylciprofloxacin (compound 3) with carbon disulfide and NaH in THF. CPF2XT was
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