Prospective of<sup>68</sup>Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation

Background Bacterial infections are still a major global healthcare problem. To combat the increasing antimicrobial resistance, early diagnosis of bacterial infections-including the identification of bacterial species-is needed to improve antibiotic stewardship and to help reduce the use of broad-spectrum antibiotics. To aid successful targeted antibiotic treatment, specific detection and localisation of infectious organisms is warranted. Nuclear medicine imaging approaches have been successfully used to diagnose bacterial infections and to differentiate between pathogen induced infections and sterile inflammatory processes. Aim In this comprehensive review we present an overview of recent developments in radiolabelled bacterial imaging tracers. Methods The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on specific imaging of bacterial using specific guidelines with MeSH-terms, truncations, and completion using cross-references. Tracers in literature that was extensively reviewed before 2016 were not included in this update. Where possible, the chemical structure of the radiolabelled compounds and clinical images were shown. Results In 219 original articles pre-clinical and clinical imaging of bacterial infection with new tracers were included. In our view, the highest translational potential lies with tracers that are specific to target the pathogens: e.g., 99m Tc-and 68 Galabelled UBI 29-41 , 99m Tc-vancomycin, m-[ 18 F]-fluoro-PABA, [methyl-11 C]-D-methionine, [ 18 F]-FDS, [ 18 F]-maltohexaose and [ 18 F]-maltotriose. An encouraging note is that some of these tracers have already been successfully evaluated in clinical settings. Conclusion This review summarises updates in tracer development for specific (pre-clinical and clinical) imaging of bacterial infections. We propsed some promising tracers that are likely to become innovative standards in the clinical setting in the near feature.

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“…This review is an update of our earlier review published in 2013 [14], as well as other thematic reviews [12,[15][16][17][18][19][20][21].…”

Section: Introductionmentioning

confidence: 95%

An update on radiotracer development for molecular imaging of bacterial infections

Welling

Hensbergen

Bunschoten

et al. 2019

Clin Transl Imaging

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“…The medicinal use of 68 Ga was rst described over 4 decades ago albeit with a very small clinical footprint for much of that time (Eder et al 2014;Graham et al 2017;Lenzo et al 2018;Velikyan 2018).…”

Section: Introductionmentioning

confidence: 99%

“…In the United States, DOTATATE labeled with 68 Ga (NETSPOT) and 177 Lu (Lutathera) by the U.S. Food and Drug Administration for NET diagnosis and therapy while, the European Union approved [ 68 Ga]DOTATOC (SomaKIT TOC) and Lutathera. Subsequent development of theranostic agents for infection/in ammation (Velikyan 2018), prostate cancer (Eder et al 2014;Lenzo et al 2018;Ruangma et al 2018), C-X-C chemokine receptor type 4 (CXCR4) (Gourni et al 2011;Herrmann et al 2016) and, most recently, broblast activation protein inhibitors (FAPI) (Kratochwil et al 2019) is further driving demand and highlights the need for access to a reliable (and economical) supply of gallium-68 that is the focus of this paper. Analogous development of a reliable pipeline of therapeutic radionuclides is also an urgent need for the nuclear medicine community (Herrmann et al 2020), but beyond the scope of this article.…”

Section: Introductionmentioning

confidence: 99%

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Rodnick

Sollert

Stark

et al. 2020

Preprint

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Purpose: To optimize the direct production of 68Ga on a cyclotron, via the 68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced 68Ga, extraction of [68Ga]GaCl3 and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module.Methods: Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2 in dilute (0.2-0.3 M) HNO3 were conducted using GE PETtrace cyclotrons and GE 68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of 67Ga through the 68Zn(p,2n)67Ga reaction without unduly compromising 68Ga yields. We also evaluated the effects of varying beam times (50-75 min) and beam currents (27-40 μA). Crude 68Ga production was measured. The extraction of [68Ga]GaCl3 was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3 was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use.Results: The decay corrected yield of 68Ga at EOB was typically >3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2 at 0.3 M HNO3. Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of 68Ga was typically >99.8% at EOB and met the requirements specified in the European Pharmacopoeia (<2% combined 66/67Ga) for a practical clinical product shelf-life. The activity yield of [68Ga]GaCl3 was typically >50% (~1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~1.67 GBq, 45mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing , and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA).Conclusion: Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional 68Ge/68Ga generators.

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“…To accommodate such needs, significant efforts have been made to realize molecular imaging in the area of infectious diseases [3,4]. Tracer developments have predominantly focused on radiopharmaceuticals (recently 1 3 reviewed in [5][6][7][8]) and on fluorescent approaches. Optical imaging of bacterial infections in vivo is emerging [9].…”

Section: Introductionmentioning

confidence: 99%

Fluorescent imaging of bacterial infections and recent advances made with multimodal radiopharmaceuticals

Welling

Hensbergen

Bunschoten

et al. 2019

Clin Transl Imaging

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Background Today, both radioactive SPECT and PET imaging radiopharmaceuticals are used for clinical diagnosis of bacterial infections. Due to the possible applications in image-guided surgery, fluorescent imaging of infections has gained interest. We here present the highlights and recent developments in the use of fluorescence imaging for bacterial infections. In this overview, we also include the latest developments in multimodal bacterial imaging strategies that combine radioactive and fluorescent imaging. Based on this literature, we present our future perspectives for the field including the translational potential. Methods In the current review, we complement earlier reports with the most recent fluorescent and multimodal radiopharmaceuticals for bacterial infection imaging. Where possible, in this review, the chemical structure of the compounds and clinical images were shown. Results A total of 35 out of 77 original articles on pre-clinical and clinical imaging of bacterial infections with fluorescent tracers and multimodality radiopharmaceuticals were included for reviewing. Conclusion In our view, the highest translational potential lies with compounds that are based on targeting vectors that are specific for bacteria: e.g., fluorescently labelled UBI 29-41 , polymyxin B, vancomycin, ZnDPA and a M. tuberculosis-specific β-lactamase-cleavable linker CNIP800. Multimodal concepts using dually labelled UBI 29-41 , vancomycin, and ZnDPA help connect optical imaging to the more traditional use of radiopharmaceuticals in infectious diseases. Multimodal bacterial imaging is a promising strategy not only to diagnose bacterial infections but also to evaluate the effectivity of surgical treatment for infections.

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Prospective of⁶⁸Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation

Cited by 38 publications

References 254 publications

An update on radiotracer development for molecular imaging of bacterial infections

An update on radiotracer development for molecular imaging of bacterial infections

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Fluorescent imaging of bacterial infections and recent advances made with multimodal radiopharmaceuticals

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Prospective of68Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation

Cited by 38 publications

References 254 publications

An update on radiotracer development for molecular imaging of bacterial infections

An update on radiotracer development for molecular imaging of bacterial infections

Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target

Fluorescent imaging of bacterial infections and recent advances made with multimodal radiopharmaceuticals

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Prospective of⁶⁸Ga Radionuclide Contribution to the Development of Imaging Agents for Infection and Inflammation