Transferrin
Transferrin is a protein involved in the transport of iron. Transferrin was labeled with 68Ga as [68Ga]apotransferrin. The tracer was found to be able to detect Staphylococcus aureus infection in a rat model within an hour of injection [78].
Nonspecific Tracers Used in Infection to Discriminate Infection from Malignancy
[18F]fluorothymidine ([18F]FLT)
Synthesis of DNA can be imaged by [18F]FLT. During an infection, microorganisms are constantly growing with actively synthesizing nucleic acids. The growth of Staphylococcus aureus in rabbit was imaged using [18F]FLT. However, nucleic acid formation is not limited to bacteria growth and makes the tracer just as nonspecific as [18F]FDG [79, 80]. In another study using a model with Yersinia enterocolitica, [18F]FLT was not useful in assessing bacterial proliferation [81].
Other clinically available PET tracers have been used in the evaluation of different aspects a particular infection. In tuberculosis, for example, [18F]NaF used to evaluate calcification of tuberculous granulomas in mice, the complex lipid covering was evaluated by [11C]choline or [18F]fluoroethylcholine. The use of these tracers is limited to the pathology of a particular infection and lacked specificity for the infection [8].
Conclusion and Future Perspective
PET imaging of infection has gained prominence over the last decade. [18F]FDG has been found useful in many site‐specific infections. It is likely to be validated in more clinical situations in the future. The introduction of PET/MRI into clinical practice may open a new chapter in infection imaging, especially where soft‐tissue definition is essential. The use microorganism‐specific tracers are being explored and the presence of longer acting PET tracer such as 64Cu and 89Zr has increased the possibilities especially in the labeling of antibodies. A lot of the tracers are at the preclinical stage of development. A lot more research is needed for the clinical application of these tracers. The search for an ideal PET tracer is still ongoing. The ideal tracer should be able to distinguish infection from inflammation, cheap, easy to prepare, and not require handling of blood products. A tracer should be able to detect both resistant and susceptible species.
Another major clinical hurdle is biofilm formation making bacteria not sensitive to anti‐bacterial agents as these agents are not able to penetrate into biofilm. Recent research on adaptive biofilm‐targeted agents can trigger development of a completely new class of imaging agents in the future.
3
Tracers used in PET imaging of infection
References
1. Sathekge M, Maes A, Van de Wiele C. FDG‐PET imaging in HIV infection and tuberculosis. Semin Nucl Med 2013;
43:349‐66.
2. Ammann RW, Stumpe KD, Grimm F, et al. Outcome after discontinuing long‐term benzimidazole treatment in 11 patients with non‐resectable alveolar echinococcosis with negative FDG‐PET/CT and anti‐EmII/3‐10 serology. PLoS Negl Trop Dis 2015; 9:e0003964.
3. Ankrah AO, Sathekge MM, Dierckx RA, Glaudemans AW. Imaging fungal infections in children. Clin Transl Imaging 2016; 4:57–72.
4. Glaudemans AW, Signore A. FDG‐PET/CT in infections: the imaging method of choice? Eur J Nucl Med Mol Imaging 2010; 37:1986‐91.
5. Auletta S, Varani M, Horvat R, Galli F, Signore A, Hess S. PET radiopharmaceuticals for specific bacteria imaging: a systematic review. J Clin Med 2019; 8:E197.
6. Heuker M, Sijbesma JWA, Suarez RA, et al. In vitro imaging of 18F‐fluorodeoxyglucose micropositron emission tomoghraphy. Sci Rep 2017; 7:4973.
7. Ankrah AO, Glaudemans AWJM, Klein HC, Dierckx RAJO, Sathekge M. The role of nuclear medicine in the staging and management of human immune deficiency virus infection and associated diseases. Nucl Med Mol Imaging 2017; 51:127–39.
8. Ankrah AO, van der Werf TS, de Vries EF, Dierckx RA, Sathekge MM, Glaudemans AW. PET/CT imaging of mycobacterium tuberculosis infection. Clin Transl Imaging. 2016; 4:131‐44.
9. Ankrah AO, Klein HC, Span LFR, et al. The role of PET in monitoring therapy in fungal infections. Curr Pharm Des 2018; 24:795–805.
10. Termaat MF, Raijmakers PG, Scholten HJ, Bakker FC, Patka P, Haarman HJ. The accuracy of diagnostic imaging for the assessment of chronic osteomyelitis: a systematic review and meta‐analysis. J Bone Joint Surg Am 2005;
87:2464‐71.
11. Stumpe KD, Zanetti M, Weishaupt D, Hodler J, Boos N, Von Schulthess GK. FDG positron emission tomography for differentiation of degenerative and infectious endplate abnormalities in the lumbar spine detected on MR imaging. AJR Am J Roentgenol 2002; 179:1151‐7.
12. Schmitz A, Risse JH, Grünwald F, Gassel F, Biersack HJ, Schmitt O. Fluorine‐18 fluorodeoxy‐glucose positron emission tomography findings in spondylodiscitis: preliminary results. Eur Spine J 2001; 10:534‐9.
13. Signore A, Jamar F, Israel O, Buscombe J, Martin‐Comin J, Lazzeri E. Clinical indications, image acquisition and data interpretation for white blood cells and anti‐granulocyte monoclonal antibody scintigraphy: an EANM procedural guideline. Eur J Nucl Med Mol Imaging 2018; 45:1816‐31.
14. Prodromou ML Ziakas PD, Poulou LS, Karsaliakos P, Thanos L, Mylonakis E. FDG PET is a robust tool for the diagnosis of spondylodiscitis: a meta‐analysis of diagnostic data. Clin Nucl Med 2014; 39:330‐5.
15. Navaz A, Torigian DA, Siegelman ES, Basu S, Chryssikos T, Alavi A. Diagnostic performance of FDG‐PET, MRI, and plain film radiography (PFR) for the diagnosis of osteomyelitis in the diabetic foot. Mol Imaging Biol 2010; 12:355‐
42.
16. Chryssikos T, Parvizi J, Ghanem E, Newberg A, Zhuang H, Alavi A. FDG‐PET imaging can diagnose periprosthetic infection of the hip. Clin Orthop Relat Res 2008; 466:1338‐42.
17. Chacko TK, Zhuang H, Stevenson K, Moussavian B, Alavi A. The importance of the location of fluorodeoxyglucose uptake in periprosthetic infection in painful hip prostheses. Nucl Med Commun 2002; 23:851‐5.
44 45
3
Chapter Three18. Vanquickenborne B, Maes A, Nuyts J, et al. The value of (18)FDG‐PET for the detection of infected hip prosthesis.
Eur J Nucl Med Mol Imaging 2003; 30:705‐15.
19. Mumme T, Reinartz P, Alfer J, Müller‐Rath R, Buell U, Wirtz DC. Diagnostic values of posittron emission tomography versus triple‐phase bone scan in hip arthroplasty loosening. Arch Orthop Trauma Surg. 2005;125:322–
9.
20. Basu S, Kwee TC, Saboury B, et al. FDG PET for diagnos‐ ing infection in hip and knee prostheses: prospective study in 221 prostheses and subgroup comparison with combined (111)In‐labeled leukocyte/(99m)Tc‐sulfur colloid bone marrow imaging in 88 prostheses. Clin Nucl Med 2014; 39:609–15.
21. Hao R, Yuan L, Kan Y, Yang J. 18F‐FDG PET for diagnosing painful arthroplasty/prosthetic joint infection. Clin Transl Imaging 2017; 5:315‐22.
22. Sah BR, Husmann L, Mayer D, et al. Diagnostic performance of 18F‐FDG‐PET/CT in vascular graft infections. Vasc Endovascular Surg 2015; 49:455‐64.
23. The 2015 ESC guidelines for the management of infective endocarditis. Eur Heart J 2015;36; 3036‐7.
24. Swart LE, Gomes A, Scholtens AM, et al. Improving the diagnostic performance of 18F‐fluorodeoxyglucose positron‐
emission tomography/computed tomography in prosthetic heart valve endocarditis. Circulation 2018; 138:1412‐
27.
25. Scarsbrook A, Barrington S. Evidence based indications for the use of PET/CT in the United Kingdom. Clin Radiol 2016; 71:e171‐88.
26. Juneau D, Golfam M, Hazra S, et al. Positron emission tomography and single‐photon emission computed tomography imaging in the diagnosis of cardiac implantable electronic device infection: a systematic review and meta‐analysis. Circ Cardiovasc Imaging 2017; 10:e005772.
27. Dumarey N, Egrise D, Blocklet D, et al. Imaging infection with 18F‐FDG‐labeled leukocyte PET/CT: initial experience in 21 patients. J Nucl Med 2006; 47:625‐32.
28. Bhattacharya A, Kochhar R, Sharma S, et al. PET/CT with 18F‐FDG‐labeled autologous leukocytes for the diagnosis of infected fluid collections in acute pancreatitis. J Nucl Med 2014;‐55:1267–72.
29. Bhargava KK, Gupta RK, Nichols KJ, Palestro CJ. In vitro human leukocyte labelling with 64Cu: an intraindividual comparison with [111In]oxine and [18F]FDG. Nucl Med Biol 2009; 36:545‐9.
30. Miñana E, Roldán M, Chivato T, Martínez T, Fuente T. Quantification of the chromosomal radiation damage induced by labelling of leukocytes with [18F]FDG. Nucl Med Biol 2015; 42:720‐3.
31. Nanni C, Errani C, Boriani L, et al. 68Ga‐citrate PET/CT for evaluating patients with infections of the bone:
preliminary results. J Nucl Med 2010; 51:1932‐6.
32. Vorster M, Maes A, van de Wiele C, Sathekge M. 68Ga‐citrate PET/CT in tuberculosis: a pilot study. Q J Nucl Med Mol Imaging 2019; 63:48‐55.
33. Salomäki SP, Kemppainen J, Hohenthal U, et al. Head‐to‐head comparison of 68Ga‐citrate and 18F‐FDG PET/CT for detection of infectious foci in patients with Staphylococcus aureus bacteraemia. Contrast Media Mol Imaging 2017;
2017:3179607.
34. Vorster M, Maes A, Jacobs A, et al. Evaluating the possible role of 68Ga‐citrate PET/CT in the characterization of indeterminate lung lesions. Ann Nucl Med 2014; 28:523‐30.
35. Ebenhan T, Zeevaart JR, Venter JD, et al. Preclinical evaluation of 68Ga‐labeled 1,4,7‐triazacyclononane‐1,4,7‐
triacetic acid‐ubiquicidin as a radioligand for PET infection imaging. J Nucl Med 2014; 55:308‐14.
36. Bhatt J, Mukherjee A, Shinto A, Karuppusamy KK, Korde A, Kumar M, et al. Gallium‐68 labeled Ubiquicidin derived octapeptide as a potential infection imaging agent. Nucl Med Biol 2018; 62‐63:47‐53.
3
Tracers used in PET imaging of infection
37. Ebenhan T, Sathekge MM, Lengana T, et al. 68Ga‐NOTA‐functionalized Ubiquicidin: cytotoxicity, biodistribution, radiation dosimetry, and first‐in‐ human PET/CT imaging of infections. J Nucl Med 2018; 59:334‐9.
38. Vilche M, Reyes AL, Vasilskis E, Oliver P, Balter H, Engler H. 68Ga‐NOTA‐UBI‐29‐41 as a PET tracer for detection of bacterial infection. J Nucl Med 2016; 57:622‐7.
39. Salber D, Gunawan J, Langen KJ, et al. Comparison of [99mTc]‐ and [18F]ubiquicidin autoradiography to anti‐
Staphylococcus aureus immunofluorescence in rat muscle abscesses. J Nucl Med 2008; 49:995‐9.
40. Ebenhan T, Mokaleng BB, Venter JD, Kruger HG, Zeevaart JR, Sathekge M. Preclinical assessment of a 68Ga‐DOTA functionalized depsipeptide as a radiodiagnostic infection imaging agent. Molecules 2017 ;22:E1403.
41. Mokaleng BB, Ebenhan T, Ramesh S, et al. Synthesis, 68Ga‐radiolabeling, and preliminary in vivo assessment of a depsipeptide‐derived compound as a potential PET/CT infection imaging agent. Biomed Res Int 2015; 2015:284354.
42. Nielsen KM, Kyneb MH, Alstrup AK, et al. (68) Ga‐labeled phage‐display selected peptides as tracers for positron emission tomography imaging of Staphylococcus aureus biofilm‐associated infections: selection, radiolabelling and pre‐ liminary biological evaluation. Nucl Med Biol 2016; 43:593‐0605.
43. Nielsen KM, Jorgensen NP, Kyneb MH, et al. Preclinical evaluation of potential infection‐imaging probe [68Ga]Ga‐
DOTA‐K‐A9 in sterile and infectious inflammation. J Label Compd Radiopharm [Internet] 2018 [cited 2019. 02.26].
https://onlinelibrary.wiley.com/doi/full/10.1002/jlcr.3640. https://doi.org/10.1002/ jlcr.3640
44. Satpati D, Arjun C, Krishnamohan R, Samuel G, Banerjee S. 68Ga‐labeled ciprofloxacin con‐ jugates as radiotracers for targeting bacterial infection. Chem Biol Drug Des 2016; 87:680‐6.
45. Langer O, Brunner M, Zeitlinger M, et al. In vitro and in vivo evaluation of [18F]ciprofloxacin for the imaging of bacterial infections with PET. Eur J Nucl Med Mol Imaging 2005; 32:143‐50.
46. Sellmyer MA, Lee I, Hou C, et al. Bacterial infection imaging with [18F]fluoropropyl‐trimethoprim. Proc Natl Acad Sci U S A 2017; 114:8372–7.
47. Eigner S, Beckford Vera D, Lebeda O, Eigner Henke K. 68Ga‐DOTA‐puromycin: in vivo imaging of bacterial infection.
J Nucl Med 2013; S54:1218.
48. Betts HM, Milicevic Sephton S, et al. Synthesis, in vitro evaluation, and radiolabeling of fluorinated puromycin analogues: potential candidates for PET imaging of protein synthesis. J Med Chem 2016; 59:9422‐30.
49. DeMarco VP, Ordonez AA, Klunk M, et al. Determination of [11C]rifampin pharmacokinetics within Mycobacterium tuberculosis‐infected mice by using dynamic positron emission tomography bioimaging. Antimicrob Agents Chemothe. 2015; 59:5768‐7.
50. Weinstein EA, Liu L, Ordonez AA, et al. Noninvasive determination of 2‐[18F]‐fluoroisonicotinic acid hydrazide pharmacokinetics by positron emission tomography in mycobacterium tuberculosis‐infected mice. Antimicrob Agents Chemother 2012; 57:6284‐90.
51. Zhang Z, Ordonez AA, Smith‐Jones P, et al. The biodistribution of 5‐[18F]fluoropyrazinamide in Mycobacterium tuberculosis‐infected mice determined by positron emission tomography. PLoS One 2017; 12:e0170871.
52. Lupetti A, Welling MM, Pauwels EK, Nibbering PH. Detection of fungal infections using radiolabeled antifungal agents. Curr Drug Targets 2005; 6:945‐54.
53. Livni E, Fischman AJ, Ray S, et al. Synthesis of 18F‐labeled fluconazole and positron emission tomography studies in rabbits. Int J Rad Appl Instrum B. 1992;19:191‐9.
54. Wiehr S, Warnke P, Rolle AM, et al. New pathogen‐ specific immunoPET/MR tracer for molecular imaging of a systemic bacterial infection. Oncotarget 2016; 7:10990‐1001.
55. Pickett JE, Thompson JM, Sadowska A, et al. Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. Bone Res 2018; 6:13.
46 47
3
Chapter Three56. Santangelo PJ, Rogers KA, Zurla C, et al. Whole‐body immunoPET reveals active SIV dynamics in viremic and antiretroviral therapy‐treated macaques. Nat Methods 2015; 12:427‐32.
57. Rolle AM, Hasenberg M, Thornton CR, et al. ImmunoPET/ MR imaging allows specific detection of Aspergillus fumigatus lung infection in vivo. Proc Natl Acad Sci U S A 2016; 113:E1026‐33.
58. Petrik M, Franssen GM, Haas H, et al. Preclinical evaluation of two 68Ga‐siderophores as potential radiopharmaceuticals for Aspergillus fumigatus infection imaging. Eur J Nucl Med Mol Imaging 2012; 39:1175‐83.
59. Petrik M, Haas H, Laverman P, et al. 68Ga‐triacetylfusarinine C and 68Ga‐ferrioxamine E for Aspergillus infection imaging: uptake specificity in various microorganisms. Mol Imaging Biol 2014; 16:102‐8.
60. Takemiya K, Ning X, Seo W, et al. Novel PET and near infrared imaging probes for the specific detection of bacterial infections associated with cardiac devices. JACC Cardiovasc Imaging 2018; 12:875‐86
61. Ning X, Seo W, Lee S, et al. PET imaging of bacterial infections with fluorine‐18 labeled maltohexaose. Angew Chem Int Ed Engl 2014; 53:14096‐101.
62. Ning X, Lee S, Wang Z, et al. Maltodextrin‐based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat Mater 2011;10:602‐7.
63. Gowrishankar G, Namavari M, Jouannot EB, et al. Investigation of 6‐[18F]‐fluoromaltose as a novel PET tracer for imaging bacterial infection. PLoS One 2014; 9:e107951.
64. Li J, Zheng H, Fodah R, Warawa JM, Ng CK. Validation of 2‐18F‐fluorodeoxysorbitol as a potential radiopharmaceutical for imaging bacterial infection in the lung. J Nucl Med 2018; 59:134‐9.
65. Ordonez AA, Weinstein EA, Bambarger LE, et al. A systematic approach for developing bacteria‐specific imaging tracers. J Nucl Med 2017; 58:144‐50.
66. Yao S, Xing H, Zhu W, et al. Infection imaging with 18F‐FDS and first‐in‐human evaluation. Nucl Med Biol 2016;
43:206‐14.
67. Weinstein EA, Ordonez AA, DeMarco VP, et al. Imaging Enterobacteriaceae infection in vivo with 18F‐
fluorodeoxysorbitol positron emission tomography. Sci Transl Med 2014; 6:259ra146.
68. Mills B, Awais RO, Luckett J, et al. [18F]FDG‐6‐P as a novel in vivo tool for imaging staphylococcal infections.
EJNMMI Res 2015; 5:13.
69. Martìnez ME, Kiyono Y, Noriki S, et al. New radiosynthesis of 2‐deoxy‐2‐[18F]fluoroacetamido‐D‐glucopyranose and its evaluation as a bacterial infections imaging agent. Nucl Med Biol 2011; 38:807‐17.
70. Peña‐Zalbidea S, Huang AY, Kavunja HW, et al. Chemoenzymatic radiosynthesis of 2‐deoxy‐2‐[18F]fluoro‐d‐
trehalose ([18F]‐2‐FDTre): a PET radioprobe for in vivo tracing of trehalose metabolism. Carbohydr Res 2019;
472:16‐22.
71. Rajamani S, Kuszpit K, Scarff JM, Lundh L, Khan M, Brown J, et al. Bioengineering of bacterial pathogens for noninvasive imaging and in vivo evaluation of therapeutics. Sci Rep 2018; 8:12618.
72. Diaz LA, Foss CA, Thornton K, et al. Imaging of muscculoskeletal bacterial infections by [124I]FIAU‐PET/CT. PLoS One 2007; 2:e1007.
73. Zhang XM, Zhang HH, McLeroth P, et al. [124I]FIAU: human dosimetry and infection imaging in patients with suspected prosthetic joint infection. Nucl Med Biol 2016; 43:273‐9.
74. Mutch CA, Ordonez AA, Qui H, et al. [11C] Para‐aminobenzoic acid: a positron emission tomography tracer targeting bacteria‐specific metabolism. ACS Infect Dis 2018; 4:1067‐72.
75. Zhang Z, Ordonez AA, Wang H, et al. Positron emission tomography imaging with 2‐[18F]F‐p‐aminobenzoic acid detects Staphylococcus aureus infections and monitors drug response. ACS Infect Dis 2018; 4:1635‐44.
3
Tracers used in PET imaging of infection
76. Neumann KD, Villanueva‐Meyer JE, Mutch CA, et al. Imaging active infection in vivo using D‐amino acid derived PET radiotracers. Sci Rep 2017; 7:7903.
77. Panizzi P, Nahrendorf M, Figueiredo JL, et al. In vivo detection of Staphylococcus aureus endocarditis by targeting pathogen‐specific prothrombin activation. Nat Med 2012; 17:1142‐6.
78. Kumar V, Boddeti DK, Evans SG, Roesch F, Howman‐Giles R. Potential use of 68Ga‐apo‐transferrin as a PET imaging agent for detecting Staphylococcus aureus infection. Nucl Med Biol 2011; 38:393‐8.
79. Jang SJ, Lee YJ, Lim S, et al. Imaging of a localized bacterial infection with endogenous thymidine kinase using radioisotope‐labeled nucleosides. Int J Med Microbiol 2012; 302:101‐7.
80. Tan Y, Liang J, Liu D, et al. 18F‐FLT PET/CT imaging in a Wister rabbit inflammation model. Exp Ther Med 2014; 8:69‐
72.
81. Wiehr S, Rolle AM, Warnke P, Kohlhofer U, Quintanilla‐Martinez L, Reischl G, et al. The positron emission tomography tracer 3′‐deoxy‐3′‐[18F]Fluorothymidine ([18F]FLT) is not suitable to detect tissue proliferation induced by systemic yersinia enterocolitica infection in mice. PLoS One 2016; 11:e0164163.
48
3
Chapter ThreeChapter 4