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Dr. Biswas received his Ph.D. from POSTECH, South Korea.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"194151",title:"Dr.",name:"Abhijit",middleName:null,surname:"Biswas",slug:"abhijit-biswas",fullName:"Abhijit Biswas",profilePictureURL:"https://mts.intechopen.com/storage/users/194151/images/system/194151.png",biography:"Dr. Abhijit Biswas is a research associate at the Indian Institute of Science Education and Research (IISER) Pune, in India. His research goal is to design and synthesize highest quality epitaxial heterostructures and superlattices, to play with their internal degrees of freedom to exploit the structure–property relationships, in order to find the next-generation multi-functional materials, in view of applications and of fundamental interest. 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1. Introduction
1.1 Enteropathogenic E. coli
Enteropathogenic E. coli (EPEC) was the first pathotype of E. coli to be associated with human disease and is a major cause of acute and chronic diarrhea in infants [1, 2]. The low microbial density of the small bowel caused by the forceful peristalsis in this part of the intestine is overcome by EPEC, which can successfully colonize the small intestine of humans [3, 4]. EPEC primarily affects children younger than 2 years old; however some outbreaks of EPEC infection in healthy adults have been associated with large inoculum ingestion [5]. The mechanism of transmission of EPEC is the fecal-oral route. In the 1940s and 1950s, EPEC was an important cause of diarrhea in developed countries with a mortality of 50% during outbreaks, but nowadays the infection by EPEC in industrial countries has a limited importance. In contrast, in low-income countries, EPEC is still an major cause of infant diarrhea [5, 6].
1.2 Hallmark of EPEC gastrointestinal infection
The phenotype that defines EPEC infection is the attaching and effacing (A/E) lesion [2, 7]. By adhering to intestinal epithelial cells, EPEC subverts cytoskeletal processes of the host cell and produces the histopathological feature of the A/E lesion. This lesion, which was first described in 1980 [8], is characterized by the intimate attachment of the bacteria to the intestinal epithelial cells and elongation and effacement of the brush border microvilli. Later on it was shown that infection is also associated with cytoskeletal rearrangements, including the accumulation of polymerized F-actin in pedestal-like structures underneath the attached bacteria [9] (Figure 1). EPEC together with enterohemorrhagic E. coli (EHEC) and Citrobacter rodentium (CR) is a member of the A/E family of bacterial pathogens that colonize the gastrointestinal tract via the A/E lesion. EPEC and EHEC are important human pathogens, while CR is a mouse-restricted pathogen [10, 11, 12, 13].
Figure 1.
Localized adherence (LA), intimate attachment, and EPEC A/E lesion formation in the intestinal epithelial surface. At an early stage, EPEC interacts in a non-intimate manner with the intestinal surface mainly through the BFP and EspA filament. After assembly of the translocation pore, EPEC injects translocated intimin receptor (Tir). Ser/Thr phosphorylation of Tir induces its anchoring in the enterocyte plasma membrane, leaving the TirM region exposed for the interaction with intimin. Subsequent Tir-intimin interaction triggers actin polymerization and pedestal formation underneath the attached bacterium. Tir phosphorylation of residue Y474 engages the host adaptor NcK, which later recruits N-WASP and WIP. N-WASP recruits the ARP2/3 complex, which induces actin nucleation and polymerization.
2. EPEC virulence factors
2.1 A pathogenicity island called LEE
The ability of EPEC to induce A/E lesions is related to a pathogenicity island (PAI) of 35 kb called the locus of enterocyte effacement (LEE) [14]. The LEE comprises 41 genes organized in 5 principal operons (LEE1-LEE5) and several smaller transcriptional units (Figure 2) [15, 16]. Orthologues of LEE are also found in other members of A/E pathogens [11]. The LEE encodes all the structural proteins necessary for the assembly of a filamentous type III secretion system (T3SS) injectisome on the bacterial cell envelope [17, 18]. The LEE also encodes transcriptional regulators (Ler, GrlR, and GrlA), translocator proteins (EspA, EspB, and EspD), six secreted effector proteins (including the translocated intimin receptor), the outer membrane protein intimin, molecular chaperones, and a lytic transglycosylase (EtgA) [19]. The mechanism of LEE regulation is complex and depends on environmental conditions, quorum sensing (QS), and several transcriptional regulators encoded within and outside the LEE [20, 21].
2.2 The type III secretion system
The type III secretion system is a macromolecular transport apparatus that is used by many gram-negative bacterial pathogens (e.g., Shigella, Yersinia, Salmonella) to translocate virulence proteins, called effectors, into the cytosol of infected cells, thereby subverting host cellular functions for the benefit of the pathogen [22]. Since pathogens use this transport apparatus to inject proteins into the host cells, this structure is also known as the injectisome. The EPEC T3SS mediates the translocation of multiple effector proteins during infection. Some of them are encoded in the LEE, whereas others are encoded outside of the LEE being generally referred to as non-LEE effectors (Nle) [23, 24]. EspA filaments link the tip of the injectisome in the bacterial cell wall to a 3–5 nm translocation pore, formed in the plasma membrane of infected cells by the translocator proteins EspB and EspD (Figure 1) [25, 26].
Figure 2.
Effectors of EPEC E2348/69. (A) Representation of the LEE island and effector genes espG, espZ, espH, map, tir, and espF. (B) Non-LEE effectors located outside the LEE are localized in integrative elements (IEs) and prophages (PPs). Effector genes are labeled in red. Pseudogenes are specified with asterisk. Scale of 5 kb is indicated at the bottom. Figure from [32].
2.3 Bundle-forming pilus (BFP)
Typical EPEC is endowed with a plasmid called pMAR2 which contains a 14-gene operon encoding the type IV pilus BFP [27, 28]. The BFP is a rope-like bundle, which allows EPEC to form microcolonies in a pattern called localized adherence and also mediates the initial interaction of bacteria with host cell surfaces (Figure 1) [29, 30, 31].
3. EPEC pathogenesis
EPEC tightly regulates its virulence genes in response to environmental conditions such as temperature [16], the increase of the pH of the small intestine [33, 34], and some hormones which are released during stress conditions [20]. Upon EPEC interaction with enterocytes, EspB and EspD proteins are inserted into the host cell membrane and assemble to form a translocation pore [25, 26]. EPEC then injects its own receptor called Tir, which is integrated into the plasma membrane in a hairpin loop topology, with the loop facing the outside of the cell where it serves as a receptor for the bacterial adhesin intimin [35, 36, 37]. Tir-intimin interaction induces clustering and dimerization of Tir, and this activates a signal cascade that starts with the phosphorylation of serine/threonine residues and leads to actin polymerization and pedestal formation underneath the attached bacterium [10, 38]. The most critical event for actin polymerization is the phosphorylation of the cytoplasmic Tir residue Y474 [39]. This induces a signal cascade which recruits the host cell adaptor Nck and N-WASP required to engage and activate the actin-nucleating ARP2/3 complex, which produces the actin nucleation and polymerization. Actin polymerization drives membrane protrusion and pedestal formation [10, 40] (Figure 1). Through the T3SS injectisome, EPEC translocates LEE-encoded effector proteins and additional effectors localized in mobile genetic element outside the LEE (Nle).
4. LEE effectors
Six effector proteins (EspG, EspZ, EspH, Map, Tir, and EspF) are encoded in the LEE island (Figure 2). Most of these, except EspZ, have important functions destabilizing the physiology of the intestinal epithelium, triggering cytoskeleton reorganization, inducing cytotoxicity and electrolyte imbalance which lead to diarrhea [11, 41]. The rapid onset of EPEC-induced diarrhea is likely induced by the cooperative action of Tir, Map, and EspF, which inhibits the sodium-D-glucose transporter (SGLT-1), the major water pump of the small intestine responsible for about 70% of the total fluid uptake [42]. In addition, Map and EspF reduce Na + absorption by the sodium-hydrogen exchanger (NHE3) [43], and EspG1/2 proteins alter the membrane targeting of the Cl-/OH-exchanger (DRA), resulting in reduced Cl-uptake. These processes result in the accumulation of salts in the gut lumen, which drives water loss from the mucosa [44].
Inhibition of endosomal trafficking by EspG1/2 reduces the level of cell surface receptors [45]. In addition, EspF and EspG induce mislocalization of aquaporins (AQP), thereby reducing epithelial water absorption [46]. Furthermore, EspB, Tir, EspF, and Map induce microvillus effacement, and this reduction of absorptive surface likely exacerbates EPEC diarrhea [47]. While EspF and Map synergistically disrupt TJs [48], EspG1/2 induces microtubule disruption contributing to TJ disruption [49]. The effector protein NleA also disrupts TJs by blocking the delivery of new TJ proteins [49, 50, 51]. The disruption of TJs increases intestinal permeability and thereby likely contributes to EPEC-induced diarrhea [52] (Figure 3).
Figure 3.
EPEC effector proteins altering epithelial cell function and inducing water loss and diarrhea. Tir, map, and EspF inhibit the sodium-D-glucose transporter. EspF reduces expression of the sodium-hydrogen exchanger NHE3. EspG and EspF induce mislocalization of aquaporins (AqP). EspG1/EspG2 alters membrane targeting of the Cl-/OH-exchanger. EspF, map, NleA, EspG1, and EspG2 disrupt tight junction complexes (TJ). EspB, Tir, EspF, and map induce microvilli effacement.
5. Non-LEE effectors
In EPEC prototype strain E2348/69, 17 functional Nle effectors are encoded in different integrative elements and prophages, frequently associated in gene clusters, with some effectors having duplicated gene copies and/or paralogs in different clusters [53] (Figure 2). EPEC infection is characterized by a weak inflammatory response [54]. Previous studies have shown that most Nle effectors and some LEE effectors inhibit the host immune response, which favors bacterial survival (Figure 4). Although NleF and NleH2 activate the NF-κB inflammatory pathway during early infection (ref), EPEC translocates several effectors that dampen the proinflammatory pathways of the cell [11]. Thus, a large number of Nle effectors inhibit host inflammation by different mechanisms, such as inhibition of the NF-κB (NleB, C, E, and H) and MAPK proinflammatory pathways (NleC and D) [55, 56, 57, 58], inhibition of the canonical (NleA) and noncanonical (NleF) inflammasomes [59], and inhibition of proliferation of lymphocytes and interleukin production (LifA) [60, 61].
Figure 4.
Schematic representation of multifunctional and overlapping effectors to control host immune response. The NF-κB proinflammatory pathway is activated by NleF and NleH2 and is inhibited by NleE, NleB, NleH1, Tir, and NleC. NleC and NleD inhibit the MAPK proinflammatory pathway. EspF, EspJ, EspH, and EspB prevent macrophage phagocytosis. NleA disrupts inflammasome activation, and LifA inhibits IL-2 and IL-4 production and lymphocyte proliferation. While EspF and map induce intrinsic apoptosis, EspZ counteracts these effects by stabilizing mitochondrial membrane potential. NleH1/NleH2 and NleF inhibit intrinsic apoptosis, and NleF, NleD, and NleB counteract extrinsic apoptosis.
The control of the epithelial cell death response to microbial infection is pivotal for pathogens and the host. Pathogens that are colonizing the epithelium need to prevent cell death to preserve their replicative foothold; by contrast, the host needs to eliminate infected cells in order to minimize tissue damage [62]. During infection of the intestinal epithelial cells, surface properties of EPEC are recognized by cell surface death receptors and induce extrinsic apoptotic pathways, while T3SS effectors (Map and EspF) trigger cytochrome c release, activation of caspases, and downstream intrinsic apoptotic pathways [11, 24]. Interestingly, early stages of apoptosis can be observed during EPEC infection, but late stages are not evident because EPEC translocates effector proteins that antagonize these pro-apoptotic effects. NleD and NleB interfere with the pro-apoptotic death receptor signaling and disrupt the downstream extrinsic apoptosis [63, 64]. NLeH1/2 and EspZ also inhibit intrinsic apoptosis and promote host cell survival [65, 66, 67] (Figure 4). NleF directly inhibits caspases involved in both intrinsic and extrinsic apoptosis pathways, including caspases 4, 8, and 9 [68]. In addition, EspZ localizes to the cytoplasmic side of the plasma membrane at the site of bacterial attachment and interacts with the translocator protein EspD. It has been proposed that EspZ indirectly prevents cell death by downregulating protein translocation and protecting cells from an overdose of effector proteins. Consistently, a ΔespZ mutant was found to be highly cytotoxic [69]. EPEC effectors are injected in a regulated manner to guarantee the success of infection. While the pro-survival effector EspZ is translocated at the early stages of infection, the pro-apoptotic effectors EspF and Map follow later [70].
6. Classical methodologies to study effector functions
Most research on EPEC effectors has been conducted by generating deletion mutants in a single or a few effector genes that are later complemented with multicopy plasmids overexpressing the effector(s). In addition, ectopic expression of individual effectors by plasmid transfection of the host cell has been applied. Both situations are prone to effector overexpression resulting in nonphysiological levels of effectors inside the host cell, which could alter effector activities. In addition, effectors often have synergistic and overlapping functions that cannot be fully appreciated by single mutations and individual transfection experiments [11, 54]. In order to overcome these limitations, we employed a marker-less gene deletion strategy to delete the whole repertoire of known effector genes found in the genome of the prototypical EPEC strain E2348/69 [32]. The genome engineering method for sequential deletion of EPEC effectors was based on the marker-less gene deletion technique described by Posfai et al. [71] and is illustrated in Figure 5.
Figure 5.
Marker-less gene deletion strategy of EPEC effector genes. Deletions using pGE-suicide plasmids with I-SceI sites and mutant alleles assembled by fusing homology regions (HRs) flanking the targeted effector gene(s). Co-integrants are identified by the Kanamycin resistance phenotype. Expression of the I-SceI in vivo from helper plasmid induces double-strand brakes that are repaired by homologous recombination. Depending on the HRs involved in this second recombination, either the WT or the mutant allele can be obtained. Figure from [32].
Using this strategy, a set of EPEC mutants with sequential deletions of effectors was generated (Table 1), ultimately resulting in strains expressing only Tir and EspZ (EPEC2), Tir (EPEC1), and the effector-less strain EPEC0 (Table 1). This approach proved to be effective to specifically modify the genome of EPEC E2348/69, avoiding the introduction of unintended alterations in the genome and leaving no sequence “scars” or antibiotic resistance genes in the chromosome as demonstrated by whole-genome sequencing [32]. Besides, the deletion mutant strains showed normal growth and maintained functional T3SS injectisomes. In addition, they allowed the translocation of individual effectors from single-copy chromosomal genes under endogenous regulation, showing the expected phenotypes without the background of the other effectors [32]. Hence these mutant strains are an excellent tool to investigate the role of individual effectors and specific combinations maintaining physiological protein levels in the context of infection.
EPEC mutant strains generated with the marker-less deletion strategy.
Encoded effectors in the indicated IEs and PPs.
7. LEE effectors are sufficient for intimate adhesion of EPEC to the epithelial cells in vitro
When EPEC bacteria adhere in vitro to cultured cells, there is an accumulation of actin filaments in the cytoplasm beneath the adherent bacteria, due to a signal cascade triggered by intimin-Tir interaction [35, 38]. Using the effector deletion mutants of EPEC, we demonstrated that the LEE effector Tir along with intimin is necessary and sufficient to induce these cytoskeletal rearrangements during in vitro infection of HeLa cells. Strains EPEC2 (bearing EspZ and Tir) and EPEC1 (bearing only Tir) were able to induce actin-pedestal formation underneath attached bacteria similar to the EPEC wild type (WT) (Figure 6). As expected because of the essential role of Tir in this process, infection of HeLa cells with the effector-less mutant EPEC0 did not induce any actin-pedestal formation (Figure 6). These data demonstrate that the individual translocation of Tir by EPEC1 is sufficient to trigger actin pedestals in HeLa cells and that non-LEE effectors are dispensable for this phenotype during in vitro infection of cultured cells.
Figure 6.
Infection of HeLa cells with EPEC WT and effector mutant strains. Immunofluorescence confocal microscopy of HeLa cells infected with EPEC WT, EPEC2, EPEC1, and EPEC0 for 1.5 h using a MOI of 200. EPEC is labeled with anti-intimin-280 serum (green), actin is stained with TRITC phalloidin (red), and cell nuclei are labeled with DAPI (gray). Actin polymerization beneath adherent bacteria is observed in EPEC WT, EPEC2, and EPEC1. Scale bar 5 μm. Figure from [32].
8. Non-LEE effectors are required for efficient A/E lesion formation in intestinal tissue
EPEC pathogenic mechanisms have been widely investigated by in vitro infection of cultured epithelial cell lines, albeit in most cases these cells are non-polarized and are not from intestinal origin. In addition, EPEC infection studies in vivo are hindered because EPEC is a human-restricted pathogen [72]. A surrogate model established to investigate A/E pathogenesis in vivo is the mouse pathogen Citrobacter rodentium (CR) [12, 13]. Although Citrobacter infection in vitro requires Tir phosphorylation for actin-pedestal formation in cell lines, Tir phosphorylation-deficient mutants still colonize the mouse gut and induce A/E lesion formation and crypt hyperplasia typical of CR infection [73]. This result highlights the necessity of a model for EPEC infection closer to the in vivo conditions in the human gut. A good established model to study EPEC-host interactions is the infection of in vitro cultured human intestinal biopsies, which allows the formation of A/E lesions undistinguishable from those observed in vivo in biopsies of patients with EPEC-induced diarrhea [4, 36, 74]. Similar to results obtained in CR-infected mice, Tir phosphorylation was not necessary for EPEC A/E lesion formation in human intestinal biopsies [75]. Surprisingly, when EPEC2 and EPEC1 deletion mutants were used to infect human duodenal biopsies, none of the infected biopsies showed A/E lesions (Table 2 and Figure 7), which contrasts with the pedestal formation observed in HeLa cells. Thus, intimin and Tir are not sufficient to induce A/E lesions in the intestinal tissue, and the IVOC model was used to identify additional LEE or non-LEE effector(s) required for A/E lesion formation. For this purpose, two additional effector mutant strains were tested: EPEC2-LEE+ (carrying all LEE effectors) and EPEC9 (carrying EspZ, Tir, and all non-LEE effectors). Whereas infection with EPEC2-LEE+ did not reveal A/E lesions, infection with EPEC9 induced A/E lesions to a similar level as the wild-type strain (Table 2 and Figure 7). It was previously reported that the LEE island is sufficient to confer the A/E phenotype to E. coli K-12 in the infection of colon carcinoma cell lines [76]. However, our results indicate that the LEE is not sufficient for A/E lesion formation in human mucosal tissue and that non-LEE effectors are required [32].
Human duodenal biopsies infected by EPEC WT and EPEC effector mutants.
Encoded effectors in the indicated IEs and PPs.
Figure 7.
Scanning electron microscopy of human duodenal biopsies infected with EPEC WT and mutant strains EPEC2, EPEC1, EPEC0, EPEC9, and EPEC2-LEE+. EPEC WT and EPEC9 induce characteristic A/E lesions with bacterial microcolony formation (asterisk) and microvilli elongation around bacterial colonies (arrowheads). In contrast, biopsies infected with EPEC2, EPEC1, EPEC0, and EPEC2-LEE+ lack adherent bacteria and A/E lesions and show a normal microvillous brush border. Scale bar 2 μm. Figure from [32].
9. Conclusions and future perspectives
The marker-less gene deletion strategy enabled the generation of effector-less strains of EPEC O127:H6 using the prototypical strain E2348/69 [32]. Given the conservation of the recombination machinery among E. coli strains, it is likely that this strategy could be applied to other A/E pathogens, E. coli pathogens, and other bacteria. The effector mutant strains can be useful to study the role of individual effectors and of combinations of effectors in pathogenesis. An individual effector or a defined combination can be inserted in the effector-less strains in their endogenous genomic loci to obtain physiological expression levels and regulation. In cell culture infections, all EPEC effector mutant strains carrying intimin and Tir were able to trigger actin-rich pedestal-like structures underneath attached bacteria. On the other hand, when the infection was performed in human intestinal tissues, translocation of Tir alone was insufficient to induce A/E lesions. Furthermore, an EPEC deletion mutant maintaining all LEE effectors and devoid of all non-LEE effectors (EPEC2-LEE+) was still unable to induce A/E lesions in human intestinal biopsies. In contrast, an EPEC strain producing the complete repertoire of non-LEE effectors and devoid of LEE effectors, except Tir and EspZ, formed A/E lesions in intestinal tissue at wild-type levels [32]. Thus, these experiments revealed that non-LEE effectors are needed for A/E lesion formation in human intestinal tissue.
In addition to their potential for basic studies, the EPEC effector mutant strains may have different applications. For instance, EPEC (and other pathogenic) strains lacking multiple effectors are likely to be strongly attenuated, but they maintain the external antigenicity of the wild-type strain. Thus, an EPEC mutant strain with a functional T3SS and the minimum set of effectors necessary to colonize the intestinal surface could be a good vaccine candidate. Further, EPEC mutant strains with the ability to attach to the human intestine could also be engineered to translocate heterologous protein antigens to generate protection against other enteric pathogens causing diarrhea, including EHEC strains [77, 78, 79, 80]. Lastly, the EPEC effector mutant strains may also have the potential to deliver therapeutic proteins to the intestinal epithelium, for instance, to combat inflammation and autoimmune disorders in the gastrointestinal tract [81].
Acknowledgments
We acknowledge support for the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI).
\n',keywords:"A/E lesion, EPEC, effectors, infection, IVOC, T3SS",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/71365.pdf",chapterXML:"https://mts.intechopen.com/source/xml/71365.xml",downloadPdfUrl:"/chapter/pdf-download/71365",previewPdfUrl:"/chapter/pdf-preview/71365",totalDownloads:247,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,dateSubmitted:"October 17th 2019",dateReviewed:"February 10th 2020",datePrePublished:"March 9th 2020",datePublished:"September 30th 2020",dateFinished:null,readingETA:"0",abstract:"Enteropathogenic E. coli (EPEC) is a diarrheagenic human pathogen. The hallmark of EPEC infection is the formation of the attaching and effacing (A/E) lesion in the intestinal epithelial cells, characterized by the effacement of brush border microvilli and the intimate bacterial attachment to the enterocyte in actin-rich pedestal-like structures. The locus of enterocyte effacement (LEE) in the EPEC genome encodes a type III protein secretion system (T3SS) that translocates multiple effector proteins into the host cell to subvert cellular functions for the benefit of the pathogen. These effectors are encoded both within and outside the LEE. In vitro cell culture infections have shown that LEE effectors are required for intimate bacterial attachment to the epithelial cells, whereas non-LEE effectors mostly play a role in modulating inflammation and cell apoptosis in the gut epithelium. We constructed a set of EPEC mutant strains harboring deletions in the complete repertoire of genes encoding T3SS effectors. Infection of human intestinal in vitro organ cultures (IVOC) with these mutant strains surprisingly revealed that non-LEE effectors are also needed to induce efficient A/E lesion formation in the intestinal mucosal tissue.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/71365",risUrl:"/chapter/ris/71365",book:{slug:"e-coli-infections-importance-of-early-diagnosis-and-efficient-treatment"},signatures:"Massiel Cepeda-Molero, Stephanie Schüller, Gad Frankel and Luis Ángel Fernández",authors:[{id:"313717",title:"Prof.",name:"Luis Ángel",middleName:null,surname:"Fernández",fullName:"Luis Ángel Fernández",slug:"luis-angel-fernandez",email:"lafdez@cnb.csic.es",position:null,institution:null},{id:"313718",title:"Dr.",name:"Massiel",middleName:null,surname:"Cepeda-Molero",fullName:"Massiel Cepeda-Molero",slug:"massiel-cepeda-molero",email:"massiel_cepeda@hotmail.com",position:null,institution:null},{id:"313719",title:"Prof.",name:"Stephanie",middleName:null,surname:"Schüller",fullName:"Stephanie Schüller",slug:"stephanie-schuller",email:"S.Schuller@uea.ac.uk",position:null,institution:null},{id:"313720",title:"Prof.",name:"Gad",middleName:null,surname:"Frankel",fullName:"Gad Frankel",slug:"gad-frankel",email:"g.frankel@imperial.ac.uk",position:null,institution:{name:"Imperial College London",institutionURL:null,country:{name:"United Kingdom"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1 Enteropathogenic E. coli",level:"2"},{id:"sec_2_2",title:"1.2 Hallmark of EPEC gastrointestinal infection",level:"2"},{id:"sec_4",title:"2. EPEC virulence factors",level:"1"},{id:"sec_4_2",title:"2.1 A pathogenicity island called LEE",level:"2"},{id:"sec_5_2",title:"2.2 The type III secretion system",level:"2"},{id:"sec_6_2",title:"2.3 Bundle-forming pilus (BFP)",level:"2"},{id:"sec_8",title:"3. EPEC pathogenesis",level:"1"},{id:"sec_9",title:"4. LEE effectors",level:"1"},{id:"sec_10",title:"5. Non-LEE effectors",level:"1"},{id:"sec_11",title:"6. Classical methodologies to study effector functions",level:"1"},{id:"sec_12",title:"7. LEE effectors are sufficient for intimate adhesion of EPEC to the epithelial cells in vitro",level:"1"},{id:"sec_13",title:"8. Non-LEE effectors are required for efficient A/E lesion formation in intestinal tissue",level:"1"},{id:"sec_14",title:"9. Conclusions and future perspectives",level:"1"},{id:"sec_15",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Kaper JB, Nataro JP, Mobley HL. Pathogenic Escherichia coli. Nature Reviews Microbiology. 2004;2:123-139'},{id:"B2",body:'Chen HD, Frankel G. Enteropathogenic Escherichia coli: Unravelling pathogenesis. FEMS Microbiology Reviews. 2005;29(1):83-98'},{id:"B3",body:'Tlaskalova-Hogenova H et al. Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunology Letters. 2004;93(2-3):97-108'},{id:"B4",body:'Hicks S et al. Role of intimin and bundle-forming pili in enteropathogenic Escherichia coli adhesion to pediatric intestinal tissue in vitro. Infection and Immunity. 1998;66(4):1570-1578'},{id:"B5",body:'Nataro JP, Kaper JB. Diarrheagenic Escherichia coli. Clinical Microbiology Reviews. 1998;11(1):142-201'},{id:"B6",body:'Ochoa TJ et al. New insights into the epidemiology of enteropathogenic Escherichia coli infection. Transactions of the Royal Society of Tropical Medicine and Hygiene. 2008;102(9):852-856'},{id:"B7",body:'Garmendia J, Frankel G, Crepin VF. Enteropathogenic and enterohemorrhagic Escherichia coli infections: Translocation, translocation, translocation. Infection and Immunity. 2005;73(5):2573-2585'},{id:"B8",body:'Ulshen MH, Rollo JL. Pathogenesis of Escherichia coli gastroenteritis in man--another mechanism. The New England Journal of Medicine. 1980;302(2):99-101'},{id:"B9",body:'Knutton S et al. Actin accumulation at sites of bacterial adhesion to tissue culture cells: Basis of a new diagnostic test for enteropathogenic and enterohemorrhagic Escherichia coli. Infection and Immunity. 1989;57(4):1290-1298'},{id:"B10",body:'Lai Y et al. Intimate host attachment: Enteropathogenic and enterohaemorrhagic Escherichia coli. Cellular Microbiology. 2013;15(11):1796-1808'},{id:"B11",body:'Wong AR et al. Enteropathogenic and enterohaemorrhagic Escherichia coli: Even more subversive elements. Molecular Microbiology. 2011;80(6):1420-1438'},{id:"B12",body:'Collins JW et al. Citrobacter rodentium: Infection, inflammation and the microbiota. Nature Reviews. Microbiology. 2014;12(9):612-623'},{id:"B13",body:'Mundy R et al. Citrobacter rodentium of mice and man. Cellular Microbiology. 2005;7(12):1697-1706'},{id:"B14",body:'McDaniel TK et al. A genetic locus of enterocyte effacement conserved among diverse enterobacterial pathogens. Proceedings of the National Academy of Sciences of the United States of America. 1995;92(5):1664-1668'},{id:"B15",body:'Elliott SJ et al. The locus of enterocyte effacement (LEE)-encoded regulator controls expression of both LEE- and non-LEE-encoded virulence factors in enteropathogenic and enterohemorrhagic Escherichia coli. Infection and Immunity. 2000;68(11):6115-6126'},{id:"B16",body:'Yerushalmi G et al. Dynamics of expression and maturation of the type III secretion system of enteropathogenic Escherichia coli. Journal of Bacteriology. 2014;196(15):2798-2806'},{id:"B17",body:'Daniell SJ et al. The filamentous type III secretion translocon of enteropathogenic Escherichia coli. Cellular Microbiology. 2001;3(12):865-871'},{id:"B18",body:'Gaytán MO et al. Type three secretion system in attaching and effacing pathogens. Frontiers in Cellular and Infection Microbiology. 2016;6:129'},{id:"B19",body:'García-Gómez E et al. The muramidase EtgA from enteropathogenic Escherichia coli is required for efficient type III secretion. Microbiology. 2011;157(Pt 4):1145-1160'},{id:"B20",body:'Franzin FM, Sircili MP. Locus of enterocyte effacement: A pathogenicity island involved in the virulence of enteropathogenic and enterohemorrhagic subjected to a complex network of gene regulation. BioMed Research International. 2015;2015:534738'},{id:"B21",body:'Furniss RCD, Clements A. Regulation of the locus of enterocyte effacement in attaching and effacing pathogens. Journal of Bacteriology. 2018;200(2):e00336-17'},{id:"B22",body:'Portaliou AG et al. Type III secretion: Building and operating a remarkable nanomachine. Trends in Biochemical Sciences. 2016;41(2):175-189'},{id:"B23",body:'Raymond B et al. Subversion of trafficking, apoptosis, and innate immunity by type III secretion system effectors. Trends in Microbiology. 2013;21(8):430-441'},{id:"B24",body:'Santos AS, Finlay BB. Bringing down the host: Enteropathogenic and enterohaemorrhagic Escherichia coli effector-mediated subversion of host innate immune pathways. Cellular Microbiology. 2015;17(3):318-332'},{id:"B25",body:'Ide T et al. Characterization of translocation pores inserted into plasma membranes by type III-secreted Esp proteins of enteropathogenic Escherichia coli. Cellular Microbiology. 2001;3(10):669-679'},{id:"B26",body:'Luo W, Donnenberg MS. Interactions and predicted host membrane topology of the enteropathogenic Escherichia coli translocator protein EspB. Journal of Bacteriology. 2011;193(12):2972-2980'},{id:"B27",body:'Stone KD et al. A cluster of fourteen genes from enteropathogenic Escherichia coli is sufficient for the biogenesis of a type IV pilus. Molecular Microbiology. 1996;20(2):325-337'},{id:"B28",body:'Brinkley C et al. Nucleotide sequence analysis of the enteropathogenic Escherichia coli adherence factor plasmid pMAR7. Infection and Immunity. 2006;74(9):5408-5413'},{id:"B29",body:'Ramboarina S et al. Structure of the bundle-forming pilus from enteropathogenic Escherichia coli. The Journal of Biological Chemistry. 2005;280(48):40252-40260'},{id:"B30",body:'Hyland RM et al. The bundlin pilin protein of enteropathogenic Escherichia coli is an N-acetyllactosamine-specific lectin. Cellular Microbiology. 2008;10(1):177-187'},{id:"B31",body:'Saldana Z et al. The Escherichia coli common Pilus and the bundle-forming Pilus act in concert during the formation of localized adherence by Enteropathogenic E. coli. Journal of Bacteriology. 2009;191(11):3451-3461'},{id:"B32",body:'Cepeda-Molero M et al. Attaching and effacing (A/E) lesion formation by enteropathogenic E. coli on human intestinal mucosa is dependent on non-LEE effectors. PLoS Pathogens. 2017;13(10):e1006706'},{id:"B33",body:'Fallingborg J. Intraluminal pH of the human gastrointestinal tract. Danish Medical Bulletin. 1999;46(3):183-196'},{id:"B34",body:'Shin S et al. An activator of glutamate decarboxylase genes regulates the expression of enteropathogenic Escherichia coli virulence genes through control of the plasmid-encoded regulator, Per. Molecular Microbiology. 2001;41(5):1133-1150'},{id:"B35",body:'Kenny B et al. Enteropathogenic E. coli (EPEC) transfers its receptor for intimate adherence into mammalian cells. Cell. 1997;91(4):511-520'},{id:"B36",body:'Frankel G et al. Generation of Escherichia coli intimin derivatives with differing biological activities using site-directed mutagenesis of the intimin C-terminus domain. Molecular Microbiology. 1998;29(2):559-570'},{id:"B37",body:'Luo Y et al. Crystal structure of enteropathogenic Escherichia coli intimin-receptor complex. Nature. 2000;405(6790):1073-1077'},{id:"B38",body:'Frankel G, Phillips AD. Attaching effacing Escherichia coli and paradigms of Tir-triggered actin polymerization: Getting off the pedestal. Cellular Microbiology. 2008;10(3):549-556'},{id:"B39",body:'Devinney R et al. Tir tyrosine phosphorylation and pedestal formation are delayed in enteropathogenic Escherichia coli sepZ::TnphoA mutant 30-5-1(3). Infection and Immunity. 2001;69(1):559-563'},{id:"B40",body:'Goosney DL, de Grado M, Finlay BB. Putting E. coli on a pedestal: A unique system to study signal transduction and the actin cytoskeleton. Trends in Cell Biology. 1999;9(1):11-14'},{id:"B41",body:'Guttman JA, Finlay BB. Subcellular alterations that lead to diarrhea during bacterial pathogenesis. Trends in Microbiology. 2008;16(11):535-542'},{id:"B42",body:'Dean P et al. Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(6):1876-1881'},{id:"B43",body:'Simpson N et al. The enteropathogenic Escherichia coli type III secretion system effector map binds EBP50/NHERF1: Implication for cell signalling and diarrhoea. Molecular Microbiology. 2006;60(2):349-363'},{id:"B44",body:'Gill RK et al. Mechanism underlying inhibition of intestinal apical Cl/OH exchange following infection with enteropathogenic E. coli. The Journal of Clinical Investigation. 2007;117(2):428-437'},{id:"B45",body:'Clements A et al. Enterohaemorrhagic Escherichia coli inhibits recycling endosome function and trafficking of surface receptors. Cellular Microbiology. 2014;16(11):1693-1705'},{id:"B46",body:'Guttman JA et al. Aquaporins contribute to diarrhoea caused by attaching and effacing bacterial pathogens. Cellular Microbiology. 2007;9(1):131-141'},{id:"B47",body:'Iizumi Y et al. The enteropathogenic E. coli effector EspB facilitates microvillus effacing and antiphagocytosis by inhibiting myosin function. Cell Host & Microbe. 2007;2(6):383-392'},{id:"B48",body:'Dean P, Kenny B. Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein. Molecular Microbiology. 2004;54(3):665-675'},{id:"B49",body:'Glotfelty LG et al. Enteropathogenic E. coli effectors EspG1/G2 disrupt microtubules, contribute to tight junction perturbation and inhibit restoration. Cellular Microbiology. 2014;16(12):1767-1783'},{id:"B50",body:'Thanabalasuriar A et al. The bacterial virulence factor NleA is required for the disruption of intestinal tight junctions by enteropathogenic Escherichia coli. Cellular Microbiology. 2010;12(1):31-41'},{id:"B51",body:'Kim J et al. The bacterial virulence factor NleA inhibits cellular protein secretion by disrupting mammalian COPII function. Cell Host & Microbe. 2007;2(3):160-171'},{id:"B52",body:'Croxen MA, Finlay BB. Molecular mechanisms of Escherichia coli pathogenicity. Nature Reviews. Microbiology. 2010;8(1):26-38'},{id:"B53",body:'Iguchi A et al. Complete genome sequence and comparative genome analysis of enteropathogenic Escherichia coli O127:H6 strain E2348/69. Journal of Bacteriology. 2009;191(1):347-354'},{id:"B54",body:'Dean P, Kenny B. The effector repertoire of enteropathogenic E. coli: Ganging up on the host cell. Current Opinion in Microbiology. 2009;12(1):101-109'},{id:"B55",body:'Baruch K et al. Metalloprotease type III effectors that specifically cleave JNK and NF-kappaB. The EMBO Journal. 2011;30(1):221-231'},{id:"B56",body:'Nadler C et al. The type III secretion effector NleE inhibits NF-kappaB activation. PLoS Pathogens. 2010;6(1):e1000743'},{id:"B57",body:'Sham HP et al. Attaching and effacing bacterial effector NleC suppresses epithelial inflammatory responses by inhibiting NF-{kappa}B and p38 mitogen-activated protein kinase activation. Infection and Immunity. 2011;79(9):3552-3562'},{id:"B58",body:'Gao X et al. NleB, a bacterial effector with glycosyltransferase activity, targets GADPH function to inhibit NF-κB activation. Cell Host & Microbe. 2013;13(1):87-99'},{id:"B59",body:'Yen H, Sugimoto N, Tobe T. Enteropathogenic Escherichia coli uses NleA to inhibit NLRP3 inflammasome activation. PLoS Pathogens. 2015;11(9):e1005121'},{id:"B60",body:'Abu-Median AB et al. Functional analysis of lymphostatin homologues in enterohaemorrhagic Escherichia coli. FEMS Microbiology Letters. 2006;258(1):43-49'},{id:"B61",body:'Klapproth JM et al. A large toxin from pathogenic Escherichia coli strains that inhibits lymphocyte activation. Infection and Immunity. 2000;68(4):2148-2155'},{id:"B62",body:'Kim M et al. Bacterial interactions with the host epithelium. Cell Host & Microbe. 2010;8(1):20-35'},{id:"B63",body:'Pearson JS et al. A type III effector antagonizes death receptor signalling during bacterial gut infection. Nature. 2013;501(7466):247-251'},{id:"B64",body:'Wong Fok Lung T et al. The cell death response to enteropathogenic Escherichia coli infection. Cellular Microbiology. 2014;16(12):1736-1745'},{id:"B65",body:'Roxas JL et al. The enteropathogenic Escherichia coli-secreted protein EspZ inhibits host cell apoptosis. Infection and Immunity. 2012;80(11):3850-3857'},{id:"B66",body:'Hemrajani C et al. NleH effectors interact with Bax inhibitor-1 to block apoptosis during enteropathogenic Escherichia coli infection. Proceedings of the National Academy of Sciences. 2010;107(7):3129-3134'},{id:"B67",body:'Royan SV et al. Enteropathogenic E. coli non-LEE encoded effectors NleH1 and NleH2 attenuate NF-kappaB activation. Molecular Microbiology. 2010;78(5):1232-1245'},{id:"B68",body:'Blasche S et al. The E. coli effector protein NleF is a Caspase inhibitor. PLoS One. 2013;8(3):e58937'},{id:"B69",body:'Berger CN et al. EspZ of enteropathogenic and enterohemorrhagic Escherichia coli regulates type III secretion system protein translocation. MBio. 2012;3(5):e00317-12'},{id:"B70",body:'Mills E et al. Real-time analysis of effector translocation by the type III secretion system of enteropathogenic Escherichia coli. Cell Host & Microbe. 2008;3(2):104-113'},{id:"B71",body:'Posfai G et al. Markerless gene replacement in Escherichia coli stimulated by a double-strand break in the chromosome. Nucleic Acids Research. 1999;27(22):4409-4415'},{id:"B72",body:'Hill SM, Phillips AD, Walker-Smith JA. Enteropathogenic Escherichia coli and life threatening chronic diarrhoea. Gut. 1991;32(2):154-158'},{id:"B73",body:'Deng W et al. Citrobacter rodentium translocated intimin receptor (Tir) is an essential virulence factor needed for actin condensation, intestinal colonization and colonic hyperplasia in mice. Molecular Microbiology. 2003;48(1):95-115'},{id:"B74",body:'Knutton S, Lloyd DR, McNeish AS. Adhesion of enteropathogenic Escherichia coli to human intestinal enterocytes and cultured human intestinal mucosa. Infection and Immunity. 1987;55(1):69-77'},{id:"B75",body:'Schüller S et al. Tir phosphorylation and Nck/N-WASP recruitment by enteropathogenic and enterohaemorrhagic Escherichia coli during ex vivo colonization of human intestinal mucosa is different to cell culture models. Cellular Microbiology. 2007;9(5):1352-1364'},{id:"B76",body:'McDaniel TK, Kaper JB. A cloned pathogenicity island from enteropathogenic Escherichia coli confers the attaching and effacing phenotype on E. coli K-12. Molecular Microbiology. 1997;23(2):399-407'},{id:"B77",body:'Riquelme-Neira R et al. Vaccination with DNA encoding truncated enterohemorrhagic Escherichia coli (EHEC) factor for adherence-1 gene (efa-1′) confers protective immunity to mice infected with E. coli O157:H7. Frontiers in Cellular and Infection Microbiology. 2016;5:104-104'},{id:"B78",body:'Szu SC, Ahmed A. Clinical studies of Escherichia coli O157:H7 conjugate vaccines in adults and young children. Microbiology Spectrum. 2014;2(6):1-7'},{id:"B79",body:'Rabinovitz BC et al. The intranasal vaccination of pregnant dams with Intimin and EspB confers protection in neonatal mice from Escherichia coli (EHEC) O157:H7 infection. Vaccine. 2016;34(25):2793-2797'},{id:"B80",body:'Marcato P et al. Recombinant Shiga toxin B-subunit-keyhole limpet hemocyanin conjugate vaccine protects mice from Shigatoxemia. Infection and Immunity. 2005;73(10):6523-6529'},{id:"B81",body:'Piñero-Lambea C, Ruano-Gallego D, Fernández LÁ. Engineered bacteria as therapeutic agents. Current Opinion in Biotechnology. 2015;35:94-102'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Massiel Cepeda-Molero",address:null,affiliation:'
Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Spain
Department of Microbial Biotechnology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CSIC), Spain
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Chisango, Agness F. Nhidza and\nAmos Marume",authors:[{id:"63704",title:"Prof.",name:"Takafira",middleName:null,surname:"Mduluza",fullName:"Takafira Mduluza",slug:"takafira-mduluza"},{id:"188575",title:"Dr.",name:"Tawanda",middleName:null,surname:"Chisango",fullName:"Tawanda Chisango",slug:"tawanda-chisango"},{id:"188576",title:"Dr.",name:"Agness",middleName:null,surname:"Nhidza",fullName:"Agness Nhidza",slug:"agness-nhidza"},{id:"188577",title:"MSc.",name:"Amos",middleName:null,surname:"Marume",fullName:"Amos Marume",slug:"amos-marume"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"73033",title:"Single-Photon Emission Computed Tomography (SPECT) Radiopharmaceuticals",doi:"10.5772/intechopen.93449",slug:"single-photon-emission-computed-tomography-spect-radiopharmaceuticals",body:'
1. Introduction
Nuclear medicine technique (NMT) is a detection process that helps in obtaining diagnostic results at molecular level of a disease. The technique is carried out by administrating target-specific radioisotope-labeled organic/biomolecule to patient and collecting the gamma signals through scintillating camera to diagnose the infected organ/tissues. In contrast to advanced instrumental procedures such as magnetic resonance imaging (MRI) and computed tomography (CT) scan, NMT offers a wide range of detection limit. For example, NMT starts working from molecular level when no morphological changes appear; however MRI and CT do this job at the appearance of morphological changes in diseased tissues.
NMT works by administration of radiolabeled molecules (commonly known as radiopharmaceuticals) to patients and acquisition of radiation collected through scintillation camera. There are two main components of radiopharmaceuticals: the organic/biomolecule and the radioisotope. The former approaches diseased cells/tissues and accumulate there at diseased cells and the latter part emits radiation to indicate the position of diseased area.
Diagnosis through NMT means the image of internal body organs like heart, kidney, lungs, breast, brain, bones, tissues, or whole body using γ-emitting radiopharmaceuticals; for example, indium-111 (111In) and technetium-99m (99mTc) labeled molecules. These radionuclides are labeled with a variety of compounds including drugs, organic species, peptides, proteins, and antibodies and then injected into the patient’s body. Intravenously administrated radiopharmaceuticals accumulate in specific body part or organ for which it is prepared and scans are obtained by single photon emission computed tomography (SPECT) camera [1]. Scan generated by SPECT camera gives very fruitful information regarding disease and tumor, which makes it easier for doctors to make decision about treatment strategies.
A large number of compounds have been labeled with γ-emitting radiotracers for imaging of different types of cancer and infection. Some of them are shown in Table 1 below [2].
Targeted agent with labeled radiotracer
Emitting radiation
Cancer type/disease
Bombesine indium-111
γ-emitting
Endocrine organ tumor
Pentadecapeptide Technetium-99m
γ-emitting
Breast and prostate cancer, gastro-entero-pancreatic tumors and lung cancer
Oxdronate-99mTc
γ-emitting
Bones disease
Tilmanocept technetium-99m
γ-emitting
Breast cancer, melanoma and oral Cavity cancer
Pertechnetate technetium-99m
γ-emitting
Urinary and bladder thyroid cancer
Iodinated bombesin I-125
γ-emitting
Endocrine cancer cell growth in endocrine organ breast, prostate, ovaries and testes
Bombesine rhenium-188
γ-emitting
Prostate tumor
FDG-F-18
γ-emitting
Soft tissue cancer and prostate cancer
Oxdronate-99mTc
γ-emitting
Bones disease
Table 1.
Gamma-emitting radiotracer for diagnostic imaging of different types of cancer and infection [1].
2. Radiopharmaceuticals
In radiopharmaceuticals, there is a radioactive component which is used for the diagnosis and treatment of different malignancies. Only 5% of radiopharmaceuticals are used for therapeutic purposes while the remaining has diagnostic applications. Radiopharmaceutical has two components: first one is pharmaceutical part and the second is radiotracer as shown in Figure 1.
Figure 1.
Radiopharmaceutical and its design.
Effectiveness of the radiopharmaceutical depends upon both parts. In order to prepare a good and efficient radiopharmaceutical, the first step involves the selection of a pharmaceutical component which is very critical [3]. Pharmaceuticals that have a preferable accumulation in targeted body organ, tissues, or cells should be selected. After the selection of pharmaceutical component, pharmaceutical is labeled with a suitable radiotracer. The radiopharmaceutical is subjected to administration after a routine quality control procedure. There are many disease targeted radiolabeled agents or compounds that are commonly used for diagnosis and therapeutic purpose. From diagnostic point of view, disease-targeted agents (either a drug or any other compound) are labeled with γ-emitting radiotracer, and for therapeutic purpose, these agents are labeled with β and α radiotracer like lutetium-177 (177Lu) and Yatrium-90 (90Y) [4]. In Table 2, some of the disease-targeted agents (radiopharmaceuticals) are shown which are used for diagnostic imaging and therapeutic purpose of different diseases and cancers.
Targeted agent with labeled radiotracer
Emitting radiation
Cancer type/disease
Metastron (89SrCl2)
β-emitting
Skeletal cancer
Radium-223 dichloride
α-emitting
Bone metastasis, breast and prostate cancer
Samarium-153-EDTMP
β-emitting
Bone and prostate cancer
Table 2.
Commonly used radiopharmaceuticals for therapeutic purpose [4].
3. SPECT—radiopharmaceuticals
Radiopharmaceuticals which are used to diagnose the cancer and infection by using the γ-emitting radionuclides such as 111In and 99mTc are known as SPECT radiopharmaceuticals. The radiotracer which is used for diagnostic purposes should have following properties [5]:
Easy availability at nuclear medicine center
Low cost
Short effective half-life then labeled pharmaceutical
Carrier free
Nontoxic
Free from α and β particles emission (with little emission)
Biological half-life not greater than time of study
Suitable energy range
Chemically reactive to form coordinate covalent bonds with the compound which is to be labeled
Common properties of γ-emitting radionuclides for SPECT imaging are given in Table 3.
γ-emitting radiotracer
Half-life (hours)
Generator
Gamma energy
Abundance of γ-emission (%age)
Indium-111
67.32
Cyclotron
0.l7l MeV 0.245 MeV
90.5 94
Technetium-99m
6.02
99mMo/99mTc
140 keV
88.9
Iodine-123
13.22
Cyclotron
159 keV
82.8
Table 3.
Common properties of γ-emitting radionuclides.
4. Characteristic of technetium-99m for labeling
More than 85% of radiopharmaceuticals which are being used to diagnose the cancer and infection are 99mTc labeled. The reason for using the 99mTc is due to following characteristics:
Half-life of technetium is 6 hours which is sufficient to examine the catabolic as well as anabolic processes which occur in patient and minimal radiation exposure time to the patients [6].
Energy of the γ-rays emitted by technetium is very low (140 keV) which does not greatly damage the soft tissues of the patient body, although they have low energy but can be detected by any sensitive gamma camera [7].
Its excretion rate from the patient body is very fast.
Its short half-life enables us to get the imaging information very quickly.
Technetium is very reactive to make complex with compounds.
Decay of technetium takes place through isomeric transitions due to which electrons and gamma radiation of low energy is emitted. Therefore, beta radiation exposure to patent is negligible.
Due to the emission of same energy levels of gamma radiation, the detector alignment becomes very accurate as no beta radiation is emitted.
Most important property of technetium is that its oxidation state can be changed according to the desired targeted body organ and parts, which makes it possible to develop a biological technetium labeled compound which can accumulate in high amount on that targeted organ and part of body which is under investigation [8].
5. Chemistry of 99mTc and oxidation state for labeling
Technetium belongs to transition metal family; its electronic configuration and physical properties are shown in table given below (Table 4). There are 22 isotopes of the technetium, but none of them is stable in nature. Half-life of 99Tc is 0.25 million years in its ground state. Oxidation state of technetium varies from −3 to +7 as shown in Table 4 below. This happens due to the 4d and 5s loss or gain of electrons by 4d orbital. Different types of ligands which are used to label the technetium and chemical conditions under which labeling process is accomplished are responsible for steadiness of such types of oxidation state. It is observed that technetium is found in nature in the form of halides (TcF6, TcCl6 and TcBr4, oxide, [TcO2, Tc2O7], sulfides [Tc2S7], and pertechnetate 99mTcO4− in +4 to +7 oxidation states). Oxidation states of smaller values such as −1, +2, +3 are naturally stabilized during complex formation with varieties of ligands; for example, +3 oxidation state is stabilized by the chelating agent, methylene diphosphate [9]. Without the use of these chelating agents in complex formation, the oxidation state will not remain constant and technetium would oxidize to +4 oxidation state and eventually change to +7 oxidation state which is most stable state in complex. The +5 and +6 oxidation of technetium is habitually charged to +4 and +7 oxidation states as shown in the following Eqs. 1 and 2 which is most stable regardless of their proportion.
Properties of technetium
Values
Atomic number
43
Atomic mass (amu)
98
Electronic configuration
1s2,2s2,2p6,3s2,3p6,3d10,4s2,4p6,4d6,5s1
Density gm/cm3 (at 25°C)
11.5
Oxidation state
−3, −1, 0, +1,+2,+3,+4,+5,+6,+7 (+4 and +7 are more stable)
Melting point in Kelvin
2430.15
Boiling point in Kelvin
5150.15
Occurrence
Solid state (naturally)
Electronagetivity
1.9
First, second, and third ionization energy (kJ/mol)
702, 1472, and 2850, respectively
Electron affinity (kJ/mol)
58
Heat of vaporization kJ/mol
660
Group
VIIB (7)
Metal category
Transitions metal
Period
Fifth
Color
Silvery gray
Numbers of isotopes
Twenty-two
Table 4.
Physical and chemical properties of technetium.
3Tc+52Tc+4+Tc+7E1
3Tc+6Tc+4+2Tc+7E2
The coordination number of the technetium during complex formation can be changed between 4 and 9.
6. Reducing agents and reduction of 99mTcO4−
Technetium generated by Moly generator presents in the form of sodium-pertechnetate (99mTc-NaTcO4). In this pertechnetate ion, the oxidation state of technetium is +7 and structure of the 99mTcO4− is pyramid tetrahedron in which Tc atom is present in the center of the tetrahedron with +7 oxidation state and four oxygen atoms located at the apexes of the triangular pyramid. This geometry and oxidation state is identical to the permanganate ion MnO4− and perrhenate ion ReO4− ion. Structure of the pertechnetate ion TcO4− is shown in Figure 2.
Figure 2.
Structure of pertechnetate ion 99mTcO4−.
Pertechnetate 99mTcO4 is a nonreactive molecule and cannot be used directly for labeling; therefore, it is necessary to reduce the pertechnetate from +7 oxidation state to lower oxidation state for labeling purposes. For the reduction of the pertechnetate 99mTcO4 form +7 oxidation state to lower oxidation state, a variety of reducing agents are employed such as stannous citrate (C12H10O14Sn3), stannous tartrate (C4H4O6Sn), stannous chloride (SnCl2.2H2O), concentrated hydrochloric acid (HCl), dithionite (O4S2−2), ferrous sulfate (FeSO4), and sodium boro tetrahdride (NaBH4). However, the most frequently used reducing agent in labeling of the compounds with technetium process is stannous chloride dihydrate (SnCl2.2H2O) [10]. Electrolysis can also be utilized as a method for reducing sodium-pertechnetate (99mTc-NaTcO4) and use zirconium as an anode and labeling compound. However, following common characteristics are being considered to choose a reducing agent in 99mTc chemistry.
It should give effectual reduction at compassionate pH environment.
It should have long shelf life mean remain unaffected when they are stored for long time.
It should not incorporate within the final product of the complex.
It should give well-defined oxidation state in order to generate intrinsic complex.
It should not interfere with complex formation procedure.
Reduction of pertechnetate 99mTcO4 with the help of stannous chloride is accomplished in acidic medium, and reaction is given below.
3Sn+23Sn+4+6eE3
299mTcO4+16H++6e99mTc+4+8H2OE4
Overall reaction
299mTcO4+16H++3Sn+299mTc+4+8H2O+3Sn+4E5
It is clear from the Eq. 4 that technetium reduces from higher oxidation state +7 to lower oxidation state +4. Under different chemical and physical conditions, other oxidation state of 99mTc such as 99mTc+3 and 99mTc+5 are likely to be formed or a mixture of all these oxidation states could possibly exist. Stannous chloride as a reducing agent is usually used in a very small amount while 99mTc is commonly administrated in the concentration ∼ 10−9 M.
7. Labeling of chelating agents with reduce technetium
Technetium-99m after reduction forms reactive species and attains the ability to bind with a variety of chelating agents to generate the labeled product. In order to form the additive bond, normally, chelating agent donates the lone pairs of the electrons to make coordinate covalent bond with 99mTc. Compounds containing the electron donating group such as carboxylic group (▬COOH), amines (▬NH2), hydroxyl (▬OH), and thiol group (▬SH) are good chelates such as DTPA (diethylenetriamine pentaacetic acid) and gluceptate.
8. Oxidation state of technetium for labeling
Technetium is found in variable oxidation states ranging from −1 to +7, but it frequently forms complexes in +5 oxidation state. A number of technetium complexes with other oxidation states also exist in increasing order [10]. Complex of technetium in +6, +2 and zero oxidation state are not synthesized because they are not fruitful for medical purpose. Different complexes of technetium that they from in different oxidation states are as follows:
Complex of technetium in +7 oxidation state (Tc+7). Technetium naturally occurs in this state, and it is most stable and nonreactive toward any chelating agent in this oxidation state. Technetium in +7 oxidation state is found in the form of technetium heptasulfide and pertechnetate 99mTcO4.
Complex of technetium in +5 oxidation state (Tc+5). Technetium is present in this oxidation state in the form of complexes such as99mTc-gluconate, 99mTc-glucepetate, and 99mTc-citrate. During these complexes formation, reduction of technetium (pertechnetate 99mTcO−4) from +7 oxidation state to lower oxidation state +5 is accomplished with stannous chloride in an aqueous medium. It is observed that technetium in +5 oxidation state have tendency to form the complex with sulfur containing molecules (dithiols) in solid state. In these sulfur complexes, four sulfur atoms are located at the corner of the square planes and oxygen atom at the apex of square pyramid. Compounds with six coordination number are preferably formed in the aqueous medium, and molecules exhibit more stable structure in the form of octahedral geometry. Diaminodithiol (DATA) is one of the best examples of such compounds. In these complexes, oxidation state of technetium is +5 and complexes are neutral and stable in this oxidation state.
Complex of technetium in +4 oxidation state (Tc+4). Oxidation state of technetium in complexes of TcO2 and hexahalo is +4. The reducing agent which is used to reduce the pertechnetate 99mTcO4 from +7 oxidation state to lower oxidation state +4 (TcO2.xH2O) is zinc with HCl. However, 20% of technetium reduces to technetium metal by this method. In technetium-99m-hydroxyethylidene diphosphonate (HEDP) complex, it is observed that the oxidation state of technetium is changeable which is highly dependent upon the pH of the method which is used to synthesize the complex. In acidic medium, the oxidation state of technetium is +3; in alkaline medium, it is +5; and in neutral medium, it is +4 [11]. This means that a slight change in pH can change the oxidation state of technetium pointing to the fact that they may exist as a mixture of all oxidation states like +3, +5 and +4 in technetium-99m-hydroxyethylidene diphosphonate (HEDP) complex.
Complex of technetium in +3 oxidation state (Tc+3). A number of technetium-99m complexes exist with +3 oxidation state in acidic medium. These complexes include DTPA (diethylenetriamine pentaacetic acid, ethylenediamine tetraacetic acid (EDTA), DMSA (dimercaptosuccinic acid) and hepatobiliary iminodiacetic acid. However, the oxidation state of technetium in the complex EDTA and DTPA become +4 in alkaline as well as in neutral medium. A variety of technetium complexes in which technetium exists in +3 oxidation state are used for myocardial scanning. These include complexes of technetium-99m with phosphine, arsine and BATOs (boronic acid adduct of technetium dioxime comples).
Complex of technetium in +1 oxidation state (Tc+1). This oxidation state is stabilized with the help of coordinate covalent bond with different types of ligands in aqueous medium. In this oxidation state, compounds are usually stable in water and air.
9. Chemistry of indium and oxidation state for labeling
Indium belongs to aluminum which are naturally occurring transition metals. Its chemical and physical properties are enlisted in Table 5. Indium is a soft silvery white metal which is not found in free elemental form but found in the form of combined state such as halides InCl3, InBr3 InI3 and InF3, sulphide and oxide (In2O3). Indium exists in three oxidation state +3, +2 and +1 but indium in +3 oxidation state it appears more stable. Thirty-nine isotopes of indium have been reported but only three isotopes such as indium-111, indium-113 and indium-115 are commonly found. Indium-111 with half-life of 66.32 hours are used in radiopharmaceutical for imaging purpose [12]. γ-radiation emitted by indium-111 have an energy of 247 keV and 172 keV and the percentage of γ-radiation emitted by indium-111 is 90.6% with minimal β-radiation emission that make the indium −111 a good imaging radiotracer.
Properties of indium
Values
Atomic number
49
Atomic mass (amu)
114.818
Electronic configuration
1s2,2s2,2p6,3s2,3p6,3d10,4s2,4p6,4d10,5s2,5p1
Density gm/cm3 (at 25°C)
7.31
Oxidation state
+1,+2,+3, (+3 more stable)
Melting point in Kelvin
429.75
Boiling point in Kelvin
2353.15
Occurrence
Solid state (naturally)
Electronegativity
1.78
First, second and third ionization energy (kJ/mol)
558, 1820, 2704, respectively
Electron affinity (kJ/mol)
29
Heat of vaporization kJ/mol
23.2
Group
IIIA (13)
Metal category
Poor metal (posttransitional)
Period
5th
Color
Silvery white
Natural isotopes (two)
Indium-113 and Indium-115
Artificial isotope
39 in number but Indium-111 and Indium-113 are important
Table 5.
Physical and chemical properties of indium.
These γ-emitting radionuclide labeled compounds can be utilized to identify the exact position and location of the infection in different parts and organs such as brain, arteries, joints, bones and tissues. In Table 6, a number of compounds bound with γ-emitting radionuclides (indium-111 and technetium-99m) along with their sensitivity and imaging purpose are shown.
General radiopharmaceuticals developed based on SPECT imaging.
Isotopic exchange
Labeling of the compounds with C-14, S-35, I-135 labeling of T3 and T4 and H-3.
Labeling with bifunctional Chelating Agent
In-111 DTPA albumin Tc-99m DTPA antibody
Introduction of foreign label
Labellng of the proteins with I-125. Tc-99m labeled radiopharmaceuticals Labeling of the hormones with I-125 Labeling of the cells with In-111 F-18 fluorodeoxyglucose
Biosynthesis
Labeling of the compounds with C-14 Co-57 cyanocobalamin Se-75 selenomethionine
Excitation labeling
Labeling of the compounds with I-223 from Xe-123 decay Labeling of the compounds with Br-77 from Kr-77 decay
Recoil labeling
Iodinated compounds Compounds label with H-3
Table 7.
Methods for labeling of the compound with radiotracers [13].
10. Methods of radiolabeling
The radiolabeling of antibiotics, drugs, peptides, proteins and organic species with different radiotracer has increased reasonably from imaging point of view in medical, biochemical and other associated fields. In the field of medical imaging, compounds are labeled with two types of radionuclides: (a) compound labeled with those radionuclide that emitted the gamma radiation and have large number of application and especially used for in vivo imaging of a number of organs and (b) secondly, the compounds are labeled with radionuclide that emitted the β-radiation and have limited in vitro study and therapeutic treatment of the disease site. During the labeling process of a compound with a radiotracer, atoms or group of atoms of compound are replaced by different or similar atoms or group of atoms of the radiotracers [13]. In order to obtain, certain type of the labeling, the labeling process is carried out under constant conditions of temperature, pressure and incubation time. There are mainly six methods for labeling of the compound with radiotracer as shown in Table 7.
SPECT-radiopharmaceuticals using Tc-99m and In-111 for cancer imaging.
11. Direct method labeling without bi-functional chelating agent
In this type of labeling process, there is no need of bi-functional chelating agents or metal cheater. These are discussed below.
11.1 Isotopes exchange labeling
In this method, some atoms from the compound which is to be labeled is replaced by isotope of the same atom of the element having different atomic mass (more or less) such as I-123, I-124, I-125, I-127, and I-131. the compound is labeled with isotope of the same element so the compound to be labeled and radiolabeled are similar in biological properties, except for the energy emitted from different isotopes of the same element which is used for labeling [14]. This method used for in vitro study. Examples of isotope exchange labeling reactions are labeling of the triiodothyronine (T3) with I-125, labeling of thyroxine with I-125, and labeling with C-14, S-35 and H-3 labeled compounds [15].
11.2 Introduction of a foreign label
In this process of labeling, a molecule of known biological function is labeled with a radionuclide. This labeling occurs by forming covalent bond or co-ordinate covalent bond. The attaché radiotracer is unknown (foreign) to the molecule, and labeling does not occur due to the exchange of its isotope. In most of these types of compounds, chelation is the cause for bond formation. In such bonds, more than one atom donates a pair of electrons to the foreign acceptor atom that is mostly a transition metal. Majority of Tc-99m labeled compounds are developed by this process such as binding of Tc-99m with DTPA, gluceptate, etc.
11.3 Biosynthesis
The biosynthesis method involves the growth of the microorganisms in a culture medium that contains the radiotracer. When microorganisms (bacteria) grow in such a medium, the radiotracer is introduced into the metabolites that are produced by the metabolic activity of the organism. This metabolite is then chemically separated. Example of such product is preparation of 57Co-B12 by using a bacterium Streptomyces griseus.
11.4 Recoil labeling
It is of limiting interest and cannot be preceded on large scale for labeling because it has low specific activity of the bounded molecule. The method involves generation of recoil ions or atoms as particles are emitted by the nucleus. These generated atoms or ions then form a bond with the targeted molecule. This high energy of recoil atoms gives poor yield.
11.5 Excitation labeling
Radioactive and very reactive daughter ions that are produced by nuclear decay process are used in excitation labeling process. In β-decay and electron capture processes, there is a production of highly energetic charged particle ions which have the ability to label the compound of interest. When Kr-77 undergoes the decay process, it yields Br-77. These (Br-77) energetic ions are able to bind the compound of interest when exposed to it [16]. A number of proteins are labeled with I-123 when protein is exposed to Xe-123 which decays into energetic I-123 and label the protein. Main disadvantage of this method is poor yield.
12. Indirect method labeling using bi-functional chelating agent
A chelating agent is a substance that has the ability to form multiple bonds with a single metal ion, thus acts as a multidendate ligand. Bi-functional chelating agent is that which has two are more separate covalent or coordinate covalent bonds with a ligand which is polydendate in nature. The labeling process using bi-functional chelating agent involves the bond formation at two sites: one bond is formed by the bi-functional chelating agent with macromolecule such as protein and antibody and other bond is formed with metal ion such as Tc-99m. There are many bi-functional chelating agents being used currently; however, most important are diethylenetriamine pentaacetic acid (DTPA), metallothionein, diamide dimercaptide (N2S2), dithiosemicarbazone, and hydrazinonicotinamide.
There are two types of labeling process by using bi-functional chelating agent.
(a) Tc-99m chelate method: In this method, a chemical is used to carry out chelation (such as diamidodithiol and cyclam) and labeling of macromolecules such as protein by forming the bond between chelating agent and protein (macromolecule).
(b) Indirect chelater antibody method: In this method, bi-functional chelating agent forms a bond with macromolecule and then it reacts with metal ion to form the complex known as metal-chelator-macromolecule complex. By using indirect chelator antibody method, a number of antibodies are labeled. The biological function of the antibodies may be affected due to the presence of the chelating agent; therefore, it is necessary to check the labeling products before a clinical trial. It is no doubt that the prelabeled chelating method gives pure metal-chelate- complex with precise structural study. However, the main drawback of this method is that it is a lengthy procedure and gives poor yield [17].
These SPECT-radiopharmaceuticals can also be developed for early and accurate diagnosis of cancer in different body parts and organs. A variety of drugs and compounds such as peptides, proteins, antibodies, and organic species were labeled with radionuclides such as indium-111 and technetium-99m, and these radiolabeled compounds are used for the successful and accurate diagnosis of different types of cancer in human and mice models [18]. In Table 8, a number of compounds which are labeled with γ-emitting radiotracer for SPECT imaging of different types of cancer with accuracy are shown.
SPECT-radiopharmaceuticals are not only used to identify infections and malignancies but are equally used to know the effectiveness of the treatment strategy which is used to cure the infections and tumors. That means, we can employ the SPECT-radiopharmaceuticals for follow-up strategy to know about the effectiveness of a treatment methods. A large numbers of radiolabeled compounds are being used to identify the effects of previous treatment strategy, for example, pentetreotide is labeled with indium-111 to follow-up of the neuroendocrine tumor therapy (tumor generated due to the hormonal cell and nerves system) in gastrointestinal tract, lungs, pancreas, and rest of the body (Table 9).
SPECT-radiopharmaceuticals using Tc-99m and In-111 for follow-up imaging.
A number of SPECT-radiopharmaceuticals are being used in clinical trials which are producing very fruitful results for the diagnosis of different types of cancers and infections in human beings (Table 10). These radiolabeled compounds help doctors obtain useful and precise information at a very early stage of the disease to identify the extent of problem and to take timely decisions about the treatment strategies.
Clinical trials study of different SPECT radiopharmaceuticals.
Future prospect
There is a need to develop more accurate, sensitive, precise, and reliable SPECT-radiopharmaceuticals to identify the malignant infections and tumors at an early stage in order to overcome the infectious diseases and cancer all over the world. If cancer is diagnosed at an early stage, it would be easier to plan the exact treatment strategy ahead of time. Considerable advancements have been made during last decades in SPECT-radiopharmaceuticals that may take the place of instrumental imaging techniques and therapeutic strategies. In combination with existing technologies, NMT may help a lot in the diagnostic and therapeutic advancement of clinical detection methods.
\n',keywords:"99mTc-antibiotics, SPECT imaging, radiopharmaceuticals, nuclear medicines, infection imaging",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73033.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73033.xml",downloadPdfUrl:"/chapter/pdf-download/73033",previewPdfUrl:"/chapter/pdf-preview/73033",totalDownloads:103,totalViews:0,totalCrossrefCites:0,dateSubmitted:"May 13th 2019",dateReviewed:"July 22nd 2020",datePrePublished:"August 21st 2020",datePublished:null,dateFinished:"August 21st 2020",readingETA:"0",abstract:"Nuclear medicine techniques have a great deal of advantage of using gamma radiation emitter radiolabeled compounds to diagnose the long list of infectious and malignant disorders in human systems. The gamma emitter radionuclide-labeled compounds are associated with single photon emission computed tomography (SPECT) camera. SPECT camera mainly offers the detection and analysis of gamma rays origin to furnish the imaging of defective organs in the body. There are about 85% radiopharmaceuticals in clinical practice which are being detected by SPECT camera. The following chapter is an update about the SPECT radiopharmaceuticals that were developed and tried for infection and cancer diagnosis.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73033",risUrl:"/chapter/ris/73033",signatures:"Syed Ali Raza Naqvi and Muhammad Babar Imran",book:{id:"7769",title:"Medical Isotopes",subtitle:null,fullTitle:"Medical Isotopes",slug:"medical-isotopes",publishedDate:"January 7th 2021",bookSignature:"Syed Ali Raza Naqvi and Muhammad Babar Imrani",coverURL:"https://cdn.intechopen.com/books/images_new/7769.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",fullName:"Syed Ali Raza Naqvi",slug:"syed-ali-raza-naqvi",email:"drarnaqvi@gmail.com",position:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"302793",title:"Dr.",name:"Muhammad Babar",middleName:null,surname:"Imran",fullName:"Muhammad Babar Imran",slug:"muhammad-babar-imran",email:"muhammadbabarimran@yahoo.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Radiopharmaceuticals",level:"1"},{id:"sec_3",title:"3. SPECT—radiopharmaceuticals",level:"1"},{id:"sec_4",title:"4. Characteristic of technetium-99m for labeling",level:"1"},{id:"sec_5",title:"5. Chemistry of 99mTc and oxidation state for labeling",level:"1"},{id:"sec_6",title:"6. Reducing agents and reduction of 99mTcO4−",level:"1"},{id:"sec_7",title:"7. Labeling of chelating agents with reduce technetium",level:"1"},{id:"sec_8",title:"8. Oxidation state of technetium for labeling",level:"1"},{id:"sec_9",title:"9. Chemistry of indium and oxidation state for labeling",level:"1"},{id:"sec_10",title:"10. Methods of radiolabeling",level:"1"},{id:"sec_11",title:"11. Direct method labeling without bi-functional chelating agent",level:"1"},{id:"sec_11_2",title:"11.1 Isotopes exchange labeling",level:"2"},{id:"sec_12_2",title:"11.2 Introduction of a foreign label",level:"2"},{id:"sec_13_2",title:"11.3 Biosynthesis",level:"2"},{id:"sec_14_2",title:"11.4 Recoil labeling",level:"2"},{id:"sec_15_2",title:"11.5 Excitation labeling",level:"2"},{id:"sec_17",title:"12. Indirect method labeling using bi-functional chelating agent",level:"1"},{id:"sec_18",title:"Future prospect",level:"1"}],chapterReferences:[{id:"B1",body:'Payolla FB et al. Radiopharmaceuticals for diagnosis in nuclear medicine: A short review. Eclética Química Journal. 2019;44:11-19'},{id:"B2",body:'Navalkissoor S et al. Single-photon emission computed tomography–computed tomography in imaging infection. Nuclear Medicine Communications. 2013;34:283-290'},{id:"B3",body:'Sathekge M et al. Molecular imaging in musculoskeletal infections with (99m)Tc-UBI 29-41 SPECT/CT. Annals of Nuclear Medicine. 2018;32(1):54-59'},{id:"B4",body:'Imam SK. Molecular nuclear imaging: The radiopharmaceuticals (review). Cancer Biotherapy & Radiopharmaceuticals. 2005;20(2):163-172'},{id:"B5",body:'Kim HO et al. Usefulness of adding SPECT/CT to 99mTc-hexamethylpropylene amine oxime (HMPAO)-labeled leukocyte imaging for diagnosing prosthetic joint infections. Journal of Computer Assisted Tomography. 2014;38(2):313-319'},{id:"B6",body:'Su H-C et al. Evaluation of 99mTc-labeled PSMA-SPECT/CT imaging in prostate cancer patients who have undergone biochemical relapse. Asian Journal of Andrology. 2017;19(3):267-271'},{id:"B7",body:'England CG et al. Molecular imaging of pancreatic cancer with antibodies. Molecular Pharmaceutics. 2016;13(1):8-24'},{id:"B8",body:'Abikhzer G, Keidar Z. SPECT/CT and tumour imaging. European Journal of Nuclear Medicine and Molecular Imaging. 2013;41(Suppl 1):S67-S80'},{id:"B9",body:'Miao Y, Benwell K, Quinn TP. 99mTc- and 111In-labeled alpha-melanocyte-stimulating hormone peptides as imaging probes for primary and pulmonary metastatic melanoma detection. Journal of Nuclear Medicine. 2007;48(1):73-80'},{id:"B10",body:'Artiko V et al. The clinical value of scintigraphy of neuroendocrine tumors using (99m)Tc-HYNIC-TOC. Journal of BUON. 2012;17(3):537-542'},{id:"B11",body:'Gabriel M et al. An intrapatient comparison of 99mTc-EDDA/HYNIC-TOC with 111In-DTPA-octreotide for diagnosis of somatostatin receptor-expressing tumors. Journal of Nuclear Medicine. 2003;44(5):708-716'},{id:"B12",body:'Cusso L et al. Combination of single-photon emission computed tomography and magnetic resonance imaging to track 111in-oxine-labeled human mesenchymal stem cells in neuroblastoma-bearing mice. Molecular Imaging. 2014;13'},{id:"B13",body:'Dar U et al. In house development of (99m)Tc-rhenium sulfide colloidal nanoparticles for sentinel lymph node detection. Pakistan Journal of Pharmaceutical Sciences. 2013;26:367-373'},{id:"B14",body:'Sadeghi S et al. Development of (111)In-labeled porphyrins for SPECT imaging. Asia Oceania Journal of Nuclear Medicine & Biology. 2014;2(2):95-103'},{id:"B15",body:'Harris TD et al. Structure-activity relationships of 111In- and 99mTc-labeled quinolin-4-one peptidomimetics as ligands for the vitronectin receptor: Potential tumor imaging agents. Bioconjugate Chemistry. 2006;17(5):1294-1313'},{id:"B16",body:'Gnanasegaran G, Ballinger JR. Molecular imaging agents for SPECT (and SPECT/CT). European Journal of Nuclear Medicine and Molecular Imaging. 2014;41(Suppl 1):S26-S35'},{id:"B17",body:'Arbab AS et al. Tracking of In-111-labeled human umbilical tissue-derived cells (hUTC) in a rat model of cerebral ischemia using SPECT imaging. BMC Medical Imaging. 2012;12(1):33'},{id:"B18",body:'Abadjian MZ, Edwards WB, Anderson CJ. Imaging the tumor microenvironment. Advances in Experimental Medicine and Biology. 2017;1036:229-257'},{id:"B19",body:'Schmitt A et al. Differences in biodistribution between 99mTc-depreotide, 111In-DTPA-octreotide, and 177Lu-DOTA-Tyr3-octreotate in a small cell lung cancer animal model. Cancer Biotherapy & Radiopharmaceuticals. 2005;20(2):231-236'},{id:"B20",body:'Aktolun C et al. Technetium-99m and indium-111 double labelling of granulocytes for kinetic and clinical studies. European Journal of Nuclear Medicine. 1995;22(4):330-334'},{id:"B21",body:'Decristoforo C et al. 99mTc-EDDA/HYNIC-TOC: A new 99mTc-labelled radiopharmaceutical for imaging somatostatin receptor-positive tumours; first clinical results and intra-patient comparison with 111In-labelled octreotide derivatives. European Journal of Nuclear Medicine. 2000;27(9):1318-1325'},{id:"B22",body:'Lebtahi R et al. Detection of neuroendocrine tumors: 99mTc-P829 scintigraphy compared with 111In-pentetreotide scintigraphy. Journal of Nuclear Medicine. 2002;43(7):889-895'},{id:"B23",body:'Palestro CJ et al. Osteomyelitis: Diagnosis with (99m)Tc-labeled antigranulocyte antibodies compared with diagnosis with (111)In-labeled leukocytes—initial experience. Radiology. 2002;223(3):758-764'},{id:"B24",body:'Storch D et al. Evaluation of [99mTc/EDDA/HYNIC0]octreotide derivatives compared with [111In-DOTA0,Tyr3, Thr8]octreotide and [111In-DTPA0]octreotide: Does tumor or pancreas uptake correlate with the rate of internalization? Journal of Nuclear Medicine. 2005;46(9):1561-1569'},{id:"B25",body:'Herlin G et al. Quantitative assessment of 99mTc-depreotide uptake in patients with non-small-cell lung cancer: Immunohistochemical correlations. Acta Radiologica. 2009;50(8):902-908'},{id:"B26",body:'Axelsson R et al. Role of scintigraphy with technetium-99m depreotide in the diagnosis and management of patients with suspected lung cancer. Acta Radiologica. 2008;49(3):295-302'},{id:"B27",body:'Shih W-J et al. 99mTc-depreotide chest SPECT demonstrates pulmonary metastases from renal cell carcinoma. Journal of Nuclear Medicine Technology. 2004;32(1):19-21'},{id:"B28",body:'Harders SW et al. Limited value of 99mTc depreotide single photon emission CT compared with CT for the evaluation of pulmonary lesions. The British Journal of Radiology. 2012;85(1015):e307-e313'},{id:"B29",body:'Szumowski P et al. Efficacy of (99m)Tc-DTPA SPECT/CT in diagnosing orbitopathy in graves’ disease. BMC Endocrine Disorders. 2019;19(1):10-10'},{id:"B30",body:'Hirschmann MT et al. Assessment of loading history of compartments in the knee using bone SPECT/CT: A study combining alignment and 99mTc-HDP tracer uptake/distribution patterns. Journal of Orthopaedic Research. 2013;31(2):268-274'},{id:"B31",body:'Alexiou GA et al. The value of 99mTc-tetrofosmin brain SPECT in predicting survival in patients with glioblastoma multiforme. Journal of Nuclear Medicine. 2010;51(12):1923-1926'},{id:"B32",body:'Merhof D et al. Optimized data preprocessing for multivariate analysis applied to 99mTc-ECD SPECT data sets of Alzheimer’s patients and asymptomatic controls. Journal of Cerebral Blood Flow and Metabolism: Official Journal of the International Society of Cerebral Blood Flow and Metabolism. 2011;31(1):371-383'},{id:"B33",body:'Ahmadzadehfar H et al. The significance of 99mTc-MAA SPECT/CT liver perfusion imaging in treatment planning for 90Y-microsphere selective internal radiation treatment. Journal of Nuclear Medicine. 2010;51(8):1206-1212'},{id:"B34",body:'Kotani K et al. Diagnostic ability of 99mTc-HSA-DTPA scintigraphy in combination with SPECT/CT for gastrointestinal bleeding. Abdominal Imaging. 2014;39(4):677-684'},{id:"B35",body:'Grosser OS et al. Pharmacokinetics of 99mTc-MAA- and 99mTc-HSA-microspheres used in preradioembolization dosimetry: Influence on the liver–lung shunt. Journal of Nuclear Medicine. 2016;57(6):925-927'},{id:"B36",body:'de Graaf W et al. 99mTc-mebrofenin hepatobiliary scintigraphy with SPECT for the assessment of hepatic function and liver functional volume before partial hepatectomy. Journal of Nuclear Medicine. 2010;51(2):229-236'},{id:"B37",body:'Santra A, Kumar R, Sharma P. Use of 99m-technetium-glucoheptonate as a tracer for brain tumor imaging: An overview of its strengths and pitfalls. Indian Journal of Nuclear Medicine: IJNM: The Official Journal of the Society of Nuclear Medicine, India. 2015;30(1):1-8'},{id:"B38",body:'Guo J et al. Cerebral infarction on 99mTc-MDP SPECT/CT imaging. Clinical Nuclear Medicine. 2013;38:925-927'},{id:"B39",body:'Yoo JM et al. Diagnosing acute pyelonephritis with CT, 99mTc-DMSA SPECT, and Doppler ultrasound: A comparative study. Korean Journal of Urology. 2010;51(4):260-265'},{id:"B40",body:'Bokhari S et al. 99mTc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses. Circulation. Cardiovascular Imaging. 2013;6(2):195-201'},{id:"B41",body:'Seo Y et al. Mapping of lymphatic drainage from the prostate using filtered 99mTc-sulfur nanocolloid and SPECT/CT. Journal of Nuclear Medicine. 2011;52(7):1068-1072'},{id:"B42",body:'Djekidel M, Brown RKJ, Piert M. Benefits of hybrid SPECT/CT for 111In-oxine- and Tc-99m-hexamethylpropylene amine oxime-labeled leukocyte imaging. Clinical Nuclear Medicine. 2011;36(7):e50-e56'},{id:"B43",body:'Yoon JK et al. In vivo tracking of 111In-labeled bone marrow mesenchymal stem cells in acute brain trauma model. Nuclear Medicine and Biology. 2010;37(3):381-388'},{id:"B44",body:'Sawada T et al. Preoperative clinical radioimmunodetection of pancreatic cancer by 111In-labeled chimeric monoclonal antibody Nd2. Japanese Journal of Cancer Research. 1999;90(10):1179-1186'},{id:"B45",body:'Zoghi M et al. Evaluation of 111In-labeled GnRH-I tracer for SPECT tumor imaging. Radiochemistry. 2019;61(2):226-232'},{id:"B46",body:'Gholamrezanezhad A et al. In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nuclear Medicine and Biology. 2011;38(7):961-967'},{id:"B47",body:'Zhu L, Ploessl K, Kung HF. PET/SPECT imaging agents for neurodegenerative diseases. Chemical Society Reviews. 2014;43(19):6683-6691'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Syed Ali Raza Naqvi",address:"draliraza@gcuf.edu.pk",affiliation:'
Department of Chemistry, Government College University, Pakistan
Punjab Institute of Nuclear Medicine (PINM), Pakistan
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