Gallium [Ga-67] citrate 205MBq/5.5ml solution for injection vials

Metals play vital roles in biological systems, with iron/heme being essential for cellular and metabolic functions necessary for survival and/or virulence in many bacterial pathogens. Given the rise of bacterial resistance to current antibiotics, there is an urgent need for the development of non-toxic and novel antibiotics that do not contribute to resistance to other antibiotics. Gallium, which mimics iron, has emerged as a promising antimicrobial agent, offering a novel approach to combat bacterial infections. Gallium does not have any known functions in biological systems. Gallium exerts its effects primarily by replacing iron in redox enzymes, effectively inhibiting bacterial growth by targeting multiple iron/heme-dependent biological processes and suppressing the development of drug resistance. The aim of this review is to highlight recent findings on the mechanisms of action of gallium and provide further insights into the development of gallium-based compounds. Understanding the mechanisms underlying gallium's biological activities is crucial for designing drugs that enhance their therapeutic therapies while minimizing side effects, offering promising avenues for the treatment of infectious diseases.

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18F-FDG PET/CT, 67Ga-citrate and white blood cell (WBC) scintigraphy are molecular imaging techniques currently used in the diagnostic workup of fever of unknown origin. However, it is unknown which technique fits which patient group best. A systematic literature search has been performed for original articles regarding the use of molecular imaging in fever of unknown origin. A total of 820 eligible studies were screened of which 63 articles evaluating 5094 patients met the inclusion criteria. 18F-FDG PET/CT provided good diagnostic accuracy (with a weighted mean sensitivity, specificity, positive predicting value, negative predictive value, accuracy and helpfulness of 84.4%, 61.8%, 80.7%, 67.8%, 76.3%, and 61.1%, respectively). Even within specific patient groups such as children, elderly, patients with connective tissue diseases, patients on renal replacement therapy, and HIV-infected patients, 18F-FDG PET/CT provided good diagnostic values. For 67Ga-citrate scintigraphy, the weighted mean sensitivity, specificity, positive predictive value, negative predictive value, and helpfulness were 42.2%, 80.3%, 82.4%, 41.9%, and 42.2%, respectively. WBC scintigraphy shows a weighted mean sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 73.5%, 86.3%, 79.1%, 82.4%, and 79.5%, respectively. However, compared to 67Ga-citrate and WBC scintigraphy, significantly more research has been performed using 18F-FDG PET/CT and 18F-FDG PET/CT has the advantage of relatively short procedural duration; it is therefore the preferred molecular diagnostic imaging technique. 67Ga-citrate and WBC scintigraphy can only be considered if 18F-FDG PET/CT is not available.

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PurposeThe angiotensin converting enzyme-2 (ACE2)-entry receptor of SARS-CoV-2-and its homologue, the angiotensin-converting enzyme (ACE), play a pivotal role in maintaining cardiovascular homeostasis. Potential changes in ACE2 expression levels and dynamics after SARS-CoV-2 infection have been barely investigated. The aim of this study was to develop an ACE2-targeting imaging agent as a noninvasive imaging tool to determine ACE2 regulation.MethodsDOTA-DX600, NODAGA-DX600 and HBED-CC-DX600 were obtained through custom synthesis and labeled with gallium-67 (T1/2 = 3.26 d) as a surrogate radioisotope for gallium-68 (T1/2 = 68 min). ACE2- and ACE-transfected HEK cells were used for the in vitro evaluation of these radiopeptides. The in vivo tissue distribution profiles of the radiopeptides were assessed in HEK-ACE2 and HEK-ACE xenografted mice and imaging studies were performed using SPECT/CT.ResultsThe highest molar activity was obtained for [67Ga]Ga-HBED-CC-DX600 (60 MBq/nmol), whereas the labeling efficiency of the other peptides was considerably lower (20 MBq/nmol). The radiopeptides were stable over 24 h in saline (> 99% intact peptide). All radiopeptides showed uptake in HEK-ACE2 cells (36-43%) with moderate ACE2-binding affinity (KD value: 83-113 nM), but no uptake in HEK-ACE cells (67Ga]Ga-DOTA-DX600 and [67Ga]Ga-NODAGA-DX600 (~ 24% IA/g), but much lower for [67Ga]Ga-HBED-CC-DX600 (7.2 ± 2.2% IA/g). SPECT/CT imaging studies confirmed the most favorable target-to-nontarget ratio for [67Ga]Ga-HBED-CC-DX600.ConclusionsThis study demonstrated ACE2 selectivity for all radiopeptides. [67Ga]Ga-HBED-CC-DX600 was revealed as the most promising candidate due to its favorable tissue distribution profile. Importantly, the HBED-CC chelator enabled 67Ga-labeling at high molar activity, which would be essential to obtain images with high signal-to-background contrast to detect (patho)physiological ACE2 expression levels in patients.

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Gallium-based therapy has been considered a potentially effective cancer therapy for decades and has recently re-emerged as a novel therapeutic strategy for the management of glioblastoma tumors. Gallium targets the iron-dependent phenotype associated with aggressive tumors by mimicking iron in circulation and gaining intracellular access through transferrin-receptor-mediated endocytosis. Mechanistically, it is believed that gallium inhibits critical iron-dependent enzymes like ribonucleotide reductase and NADH dehydrogenase (electron transport chain complex I) by replacing iron and removing the ability to transfer electrons through the protein secondary structure. However, information regarding the effects of gallium on cellular iron metabolism is limited. As mitochondrial iron metabolism serves as a central hub of the iron metabolic network, the goal of this study was to investigate the effects of gallium on mitochondrial iron metabolism in glioblastoma cells. Here, it has been discovered that gallium nitrate can induce mitochondrial iron depletion, which is associated with the induction of DNA damage. Moreover, the generation of gallium-resistant cell lines reveals a highly unstable phenotype characterized by impaired colony formation associated with a significant decrease in mitochondrial iron content and loss of the mitochondrial iron uptake transporter, mitoferrin-1. Moreover, gallium-resistant cell lines are significantly more sensitive to radiation and have an impaired ability to repair any sublethal damage and to survive potentially lethal radiation damage when left for 24 h following radiation. These results support the hypothesis that gallium can disrupt mitochondrial iron metabolism and serve as a potential radiosensitizer.

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Positron emission tomography (PET) is a noninvasive molecular imaging method extensively applied in the detection and treatment of various diseases. Hypoxia is a common phenomenon found in most solid tumors. Nitroimidazole is a group of bioreducible pharmacophores that selectively accumulate in hypoxic regions of the body. Over the past few decades, many scientists have reported the use of radiopharmaceuticals containing nitroimidazole for the detection of hypoxic tumors. Gallium-68, a positron-emitting radioisotope, has a favorable half-life time of 68 min and can be conveniently produced by 68Ge/68Ga generators. Recently, there has been significant progress in the preparation of novel 68Ga-labeled complexes bearing nitroimidazole moieties for the diagnosis of hypoxia. This review provides a comprehensive overview of the current status of developing 68Ga-labeled radiopharmaceuticals with nitroimidazole moieties, their pharmacokinetics, and in vitro and in vivo studies, as well as PET imaging studies for hypoxic tumors.

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Pathogenic Staphylococcus aureus causes most infectious disease related deaths in the developed world. Continuously evolving resistance to clinically approved antibiotics and combination therapies limits treatment efficacy; new strategies that evade and slow resistance or produce resistant mutants with reduced fitness are needed. We employ antibiotics conjugated to bacterially recognized siderophores to potentiate their efficacy. Acting as a Trojan horse, the siderophore antibiotic conjugates efficiently deliver the antibiotic inside the bacterial cytoplasm by hijacking the iron transport system pathways which are crucial for bacterial survival. Here, we investigated the mechanism of action of gallium xenometallomycins (siderophore antibiotic conjugates incorporating non-endogenous metal ions), Ga-DFO-Cip and Ga-LDFC-Cip, which have demonstrated high potency compared to the parent antibiotic's efficacy in vitro in S. aureus infection. Employing physicochemical, synthetic and transcriptomic analysis studies, this work reveals that kinetically inert, gallium-containing xenometallomycins targeting cytoplasmic bacterial targets impart differential resistance and gene expression profiles when compared to their parent antibiotic in S. aureus bacterial strains. Both Ga-DFO-Cip and Ga-LDFC-Cip effectively disrupt iron-siderophore biosynthesis and uptake machinery. We affirm our results with the radioactive surrogate 67/68Ga-DFO-Cip and demonstrate that the bacterial uptake in Ga-DFO-Cip-resistant S. aureus strains is impaired, leading to diminished compound accumulation in vitro and in vivo.

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Gallium-68-labeled siderophores as radiotracers have gained interest for the development of in situ infection-specific imaging diagnostics. Here, we report radiolabeling, in vitro screening, and in vivo pharmacokinetics (PK) of gallium-68-labeled schizokinen ([68Ga]Ga-SKN) as a new potential radiotracer for imaging bacterial infections. We radiolabeled SKN with ≥95% radiochemical purity. Our in vitro studies demonstrated its hydrophilic characteristics, neutral pH stability, and short-term stability in human serum and toward transchelation. In vitro uptake of [68Ga]Ga-SKN by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and S. epidermidis, but no uptake by Candida glabrata, C. albicans, or Aspergillus fumigatus, demonstrated its specificity to bacterial species. Whole-body [68Ga]Ga-SKN positron emission tomography (PET) combined with computerized tomography (CT) in healthy mice showed rapid renal excretion with no or minimal organ uptake. The subsequent ex vivo biodistribution resembled this fast PK with rapid renal excretion with minimal blood retention and no major organ uptake and showed some dissociation of the tracer in the urine after 60 min postinjection. These findings warrant further evaluation of [68Ga]Ga-SKN as a bacteria-specific radiotracer for infection imaging.

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PurposePositron emission tomography remains the most important medical imaging technique for noninvasive imaging. Advances in radiotracer design, particularly those based on antibody(-formats), have broadened diagnostic applications. While minibodies and nanobodies stand out among antibody-type radiotracers due to their unique characteristics and pharmacokinetics, a direct comparison between these formats remains unexplored. In this study, we generated a so-called minabody, a minibody-like protein consisting of a nanobody fused to a CH3 domain, and compared it with its nanobody counterpart in vitro and in vivo upon labeling with various PET radionuclides.MethodsA previously developed human TIGIT-targeting nanobody was reformatted to a minabody format to allow head-to-head comparison of both formats. The minabody and nanobody formats were compared in vitro for binding, specificity and stability. The minabody and/or nanobody formats were labeled with copper-64, gallium-68 or fluor-18 for non-invasive imaging of human TIGIT-expressing tumors by PET/CT over time.ResultsThe minabody format showed higher binding affinities compared to the nanobody format. Despite lower binding affinity, the nanobody format outperformed the minabody format as PET imaging tracer showing higher specificity and allowing imaging of human TIGIT expression from 1 to 48 h post-injection upon labeling with copper-64. In addition, copper-64 showed superior tumor uptake and contrast for nanobody imaging compared to gallium-68 and fluor-18.ConclusionThis study describes the first head-to-head comparison between the minibody and nanobody format for PET imaging. Our results underscore the importance of considering both targeting vector format and the radionuclide to achieve accurate and high-quality PET imaging.

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KP46 (tris(hydroxyquinolinato)gallium(III)) is an experimental, orally administered anticancer drug. Its absorption, delivery to tumours, and mode of action are poorly understood. We aimed to gain insight into these issues using gallium-67 and gallium-68 as radiotracers with SPECT and PET imaging in mice. [67Ga]KP46 and [68Ga]KP46, compared with [68Ga]gallium acetate, were used for logP measurements, in vitro cell uptake studies in A375 melanoma cells, and in vivo imaging in mice bearing A375 tumour xenografts up to 48 h after intravenous (tracer level) and oral (tracer and bulk) administration. 68Ga was more efficiently accumulated in A375 cells in vitro when presented as [68Ga]KP46 than as [68Ga]gallium acetate, but the reverse was observed when intravenously administered in vivo. After oral administration of [68/67Ga]KP46, absorption of 68Ga and 67Ga from the GI tract and delivery to tumours were poor, with the majority excreted in faeces. By 48 h, low but measurable amounts were accumulated in tumours. The distribution in tissues of absorbed radiogallium and octanol extraction of tissues suggested trafficking as free gallium rather than as KP46. We conclude that KP46 likely acts as a slow releaser of gallium ions which are inefficiently absorbed from the GI tract and trafficked to tissues, including tumour and bone.

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