Imaging zinc trafficking <i>in vivo</i> by positron emission tomography with zinc-62

Firth, George; Yu, Zilin; Bartnicka, Joanna Julia; Parker, David J.; Kim, Jana; Sunassee, Kavitha; Greenwood, Hannah E.; Al-Salamee, Fahad; Jauregui-Osoro, Maite; Pietro, A. Di; Guzman, Joanna; Blower, Philip J.

doi:10.1093/mtomcs/mfac076

Cited by 5 publications

(7 citation statements)

References 55 publications

(47 reference statements)

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“…Therefore, the impact of the R138X variant on global zinc trafficking was also studied. PET images revealed the typical biodistribution for 62 Zn and 63 Zn as seen in previous studies in mice and humans (7,10,11), including uptake in the heart, liver, kidneys, pancreas, intestines, and salivary glands (Figure 1A). PET quantification in all three groups revealed that 62 Zn is rapidly cleared within minutes from the blood following i.v.…”

Section: Kinetic Delivery Of Zinc From Blood To Tissues Over 1 H Rema...supporting

confidence: 73%

“…[ 62 Zn]Zn-citrate was produced as previously described (7). In brief, this was achieved by proton irradiation (27 MeV,35 µA for 9 h) of a copper foil target that was subsequently dissolved in concentrated hydrochloric acid and hydrogen peroxide.…”

Section: Production Of 62 Zn For Pet Imagingmentioning

confidence: 99%

“…Recent developments in imaging technology are making testing of hypotheses such as this possible. We have previously shown the potential of the positron-emitting zinc radioisotope 62 Zn for non-invasively monitoring zinc trafficking in vivo beyond 1 day with PET imaging (7,8). Here, we describe the application of 62 Zn to measure zinc dynamics, combined with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation-ICP-MS (LA-ICP-MS), which maps static metal quantity at cellular resolution.…”

Section: Introductionmentioning

confidence: 99%

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Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice

et al. 2023

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IntroductionCommon variants in the SLC30A8 gene, encoding the secretory granule zinc transporter ZnT8 (expressed largely in pancreatic islet alpha and beta cells), are associated with altered risk of type 2 diabetes. Unexpectedly, rare loss-of-function (LoF) variants in the gene, described in heterozygous individuals only, are protective against the disease, even though knockout of the homologous SLC30A8 gene in mice leads to unchanged or impaired glucose tolerance. Here, we aimed to determine how one or two copies of the mutant R138X allele in the mouse SLC30A8 gene impacts the homeostasis of zinc at a whole-body (using non-invasive 62Zn PET imaging to assess the acute dynamics of zinc handling) and tissue/cell level [using laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to map the long-term distribution of zinc and manganese in the pancreas].MethodsFollowing intravenous administration of [62Zn]Zn-citrate (~7 MBq, 150 μl) in wild-type (WT), heterozygous (R138X+/−), and homozygous (R138X+/+) mutant mice (14–15 weeks old, n = 4 per genotype), zinc dynamics were measured over 60 min using PET. Histological, islet hormone immunohistochemistry, and elemental analysis with LA-ICP-MS (Zn, Mn, P) were performed on sequential pancreas sections. Bulk Zn and Mn concentration in the pancreas was determined by solution ICP-MS.ResultsOur findings reveal that whereas uptake into organs, assessed using PET imaging of 62Zn, is largely unaffected by the R138X variant, mice homozygous of the mutant allele show a substantial lowering (to 40% of WT) of total islet zinc, as anticipated. In contrast, mice heterozygous for this allele, thus mimicking human carriers of LoF alleles, show markedly increased endocrine and exocrine zinc content (1.6-fold increase for both compared to WT), as measured by LA-ICP-MS. Both endocrine and exocrine manganese contents were also sharply increased in R138X+/− mice, with smaller increases observed in R138X+/+ mice.DiscussionThese data challenge the view that zinc depletion from the beta cell is the likely underlying driver for protection from type 2 diabetes development in carriers of LoF alleles. Instead, they suggest that heterozygous LoF may paradoxically increase pancreatic β-cell zinc and manganese content and impact the levels of these metals in the exocrine pancreas to improve insulin secretion.

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Section: Kinetic Delivery Of Zinc From Blood To Tissues Over 1 H Rema...supporting

confidence: 73%

Section: Production Of 62 Zn For Pet Imagingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice

et al. 2023

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“…General Information Zinc (Zn) exists in three positron-emitting isotopes ( 62/63/65 Zn) that have the potential to be used as PET biomarkers of zinc trafficking in various pathological conditions [182]. Among them, 62 Zn has limited use because it decays to another positron-emitting isotope, 62 Cu (β + = 98%; t 1/2 = 9.7 min), which could confound the image interpretation of PET scans [182]. Nevertheless, 62 Zn has been used preclinically to image zinc transport in pancreatic exocrine function [183].…”

Section: Production and Availabilitymentioning

confidence: 99%

“…Among the Zn PET isotopes, 65 Zn has the longest half-life (t 1/2 = 243.9 d), making it unsuitable for diagnostic imaging because it will cause high radiation exposure to patients over time [182]. 63 Zn has a favorable decay characteristic (β + = 93%; t 1/2 = 38.47 min) for diagnostic imaging and pharmacokinetic studies [184,185].…”

Section: Production and Availabilitymentioning

confidence: 99%

Radiometals in Imaging and Therapy: Highlighting Two Decades of Research

Sharma,

Pandey

2023

Pharmaceuticals

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The present article highlights the important progress made in the last two decades in the fields of molecular imaging and radionuclide therapy. Advancements in radiometal-based positron emission tomography, single photon emission computerized tomography, and radionuclide therapy are illustrated in terms of their production routes and ease of radiolabeling. Applications in clinical diagnostic and radionuclide therapy are considered, including human studies under clinical trials; their current stages of clinical translations and findings are summarized. Because the metalloid astatine is used for imaging and radionuclide therapy, it is included in this review. In regard to radionuclide therapy, both beta-minus (β−) and alpha (α)-emitting radionuclides are discussed by highlighting their production routes, targeted radiopharmaceuticals, and current clinical translation stage.

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Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

Lockwood

2024

Biometals

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Independent trials indicate that either oral Zn2+ or metformin can separately improve COVID-19 outcomes by approximately 40%. Coordination chemistry predicts a mechanistic relationship and therapeutic synergy. Zn2+ deficit is a known risk factor for both COVID-19 and non-infectious inflammation. Most dietary Zn2+ is not absorbed. Metformin is a naked ligand that presumably increases intestinal Zn2+ bioavailability and active absorption by cation transporters known to transport metformin. Intracellular Zn2+ provides a natural buffer of many protease reactions; the variable “set point” is determined by Zn2+ regulation or availability. A Zn2+-interactive protease network is suggested here. The two viral cysteine proteases are therapeutic targets against COVID-19. Viral and many host proteases are submaximally inhibited by exchangeable cell Zn2+. Inhibition of cysteine proteases can improve COVID-19 outcomes and non-infectious inflammation. Metformin reportedly enhances the natural moderating effect of Zn2+ on bioassayed proteome degradation. Firstly, the dissociable metformin–Zn2+ complex could be actively transported by intestinal cation transporters; thereby creating artificial pathways of absorption and increased body Zn2+ content. Secondly, metformin Zn2+ coordination can create a non-natural protease inhibitor independent of cell Zn2+ content. Moderation of peptidolytic reactions by either or both mechanisms could slow (a) viral multiplication (b) viral invasion and (c) the pathogenic host inflammatory response. These combined actions could allow development of acquired immunity to clear the infection before life-threatening inflammation. Nirmatrelvir (Paxlovid®) opposes COVID-19 by selective inhibition the viral main protease by a Zn2+-independent mechanism. Pending safety evaluation, predictable synergistic benefits of metformin and Zn2+, and perhaps metformin/Zn2+/Paxlovid® co-administration should be investigated.

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Imaging zinc trafficking in vivo by positron emission tomography with zinc-62

Cited by 5 publications

References 55 publications

Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice

Impact of an SLC30A8 loss-of-function variant on the pancreatic distribution of zinc and manganese: laser ablation-ICP-MS and positron emission tomography studies in mice

Radiometals in Imaging and Therapy: Highlighting Two Decades of Research

Coordination chemistry suggests that independently observed benefits of metformin and Zn2+ against COVID-19 are not independent

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