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Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets.

ABSTRACT: The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. Among nuclear imaging tools, radiolabeled antibiotics traditionally have lacked the sensitivity or specificity necessary to diagnose bacterial infections accurately. One reason for the lack of success is that the antibiotics were often chelated to a radiometal. This was done without addressing the ramifications of how the radiolabeling would impact probe entry to the bacterial cell, or the mechanism of binding to an intracellular target. In this review, we approach bacterial infection imaging through the lens of bacterial specific molecular targets, their intracellular or extracellular location, and discuss radiochemistry strategies to guide future probe development.

SUBMITTER: Northrup JD

PROVIDER: S-EPMC6888724 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets.

Northrup Justin D JD Mach Robert H RH Sellmyer Mark A MA

International journal of molecular sciences 20191119 22

The discovery of penicillin began the age of antibiotics, which was a turning point in human healthcare. However, to this day, microbial infections are still a concern throughout the world, and the rise of multidrug-resistant organisms is an increasing challenge. To combat this threat, diagnostic imaging tools could be used to verify the causative organism and curb inappropriate use of antimicrobial drugs. Nuclear imaging offers the sensitivity needed to detect small numbers of bacteria in situ. ...[more]

PMID: 31752318

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Project description:BackgroundTerbium-155 [T1/2 = 5.32 d, Eγ = 87 keV (32%) 105 keV (25%)] is an interesting radionuclide suitable for single photon emission computed tomography (SPECT) imaging with potential application in the diagnosis of oncological disease. It shows similar decay characteristics to the clinically established indium-111 and would be a useful substitute for the diagnosis and prospective dosimetry with biomolecules that are afterwards labeled with therapeutic radiolanthanides and pseudo-radiolanthanides, such as lutetium-177 and yttrium-90. Moreover, terbium-155 could form part of the perfect "matched pair" with the therapeutic radionuclide terbium-161, making the concept of true radiotheragnostics a reality. The aim of this study was the investigation of the production of terbium-155 via the 155Gd(p,n)155Tb and 156Gd(p,2n)155Tb nuclear reactions and its subsequent purification, in order to obtain a final product in quantity and quality sufficient for preclinical application. The 156Gd(p,2n)155Tb nuclear reaction was performed with 72 MeV protons (degraded to ~ 23 MeV), while the 155Gd(p,n)155Tb reaction was degraded further to ~ 10 MeV, as well as performed at an 18 MeV medical cyclotron, to demonstrate its feasibility of production.ResultThe 156Gd(p,2n)155Tb nuclear reaction demonstrated higher production yields of up to 1.7 GBq, however, lower radionuclidic purity when compared to the final product (~ 200 MBq) of the 155Gd(p,n)155Tb nuclear reaction. In particular, other radioisotopes of terbium were produced as side products. The radiochemical purification of terbium-155 from the target material was developed to provide up to 1.0 GBq product in a small volume (~ 1 mL 0.05 M HCl), suitable for radiolabeling purposes. The high chemical purity of terbium-155 was proven by radiolabeling experiments at molar activities up to 100 MBq/nmol. SPECT/CT experiments were performed in tumor-bearing mice using [155Tb]Tb-DOTATOC.ConclusionThis study demonstrated two possible production routes for high activities of terbium-155 using a cyclotron, indicating that the radionuclide is more accessible than the exclusive mass-separated method previously demonstrated. The developed radiochemical purification of terbium-155 from the target material yielded [155Tb]TbCl3 in high chemical purity. As a result, initial cell uptake investigations, as well as SPECT/CT in vivo studies with [155Tb]Tb-DOTATOC, were successfully performed, indicating that the chemical separation produced a product with suitable quality for preclinical studies.

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Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets.

Publications

Radiochemical Approaches to Imaging Bacterial Infections: Intracellular versus Extracellular Targets.

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